AU2006208630B2 - SPM 927 for add-on therapy of schizophrenia - 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

WO 2006/079547 PCT/EP2006/000722 Lacosamide for add-on-therapy Description 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 5 with antipsychotics, in particular psychosis, more particular schizophrenia, in an add-on therapy to at least one antipsychotic. Particularly, the present invention is directed to the use of a class of peptide compounds for the prevention, alleviation or/and treatment of schizophrenia, 10 bipolar disorder, autism, attention deficit hyperactivity disorder, psychosis, psychosis associated with schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and alcohol abuse, affective disorders, dyskinesias and related disorders, dementia, mental retardation, polydipsia/hyponatraemia, severe personality 15 disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's syndrom, Parkinson's disease, or/and dopaminergic therapy of Parkinson's disease, preferably wherein psychosis is associated with schizophrenia, in an add-on therapy-to at least one antipsychotic. 20 Certain peptides are known to exhibit central nervous system (CNS) activity and are useful in the treatment of epilepsy and other CNS disorders. These peptides which are described in the U.S. Patent No. 5,378,729 have the Formula (Ia): 25 30 WO 2006/079547 PCT/EP2006/000722 -2

R

2 R--NH-[-C- CNH-] r-C- R 1 5 0~~ )

R

3 Formula (la) 10 wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is 15 substituted with at least one electron withdrawing group or electron 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 20 lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; and

R

2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower 25 alkyl heterocyclic, 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 0, S, S(O)., NR 4 , PR 4 or a chemical bond; 30 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo, Z is a chemical bond, or 35 WO 2006/079547 PCT/EP2006/000722 -3 ZY taken together is NR 4 NRR, NR 4

OR

5 , ONR 4

R

7 , OPR 4

R

5 , PR 4

OR

5 ,

SNR

4

R

7 , NR4SR 7 , SPR 4 RS or PR 4

SR

7 , NR 4 PRR or PR 4

NRSR

7 , 5 NR 4 C-RS, SCR 5 , NR 4 C-OR, SC-OR; 0 0 0 U

R

4 , R 5 and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, 10 lower alkenyl, or lower alkynyl, wherein R 4 , R 5 and R may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and

R

7 is R 6 or COOR or CORB; 15

R

8 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 an electron donating group; and 20 n is 1-4; and a is 1-3. U.S. Patent No. 5,773,475 also discloses additional compounds useful for treating CNS disorders. These compounds are N-benzyl-2-amino-3 25 methoxy-propionamide having the Formula (Ila): H H H I I I Ar-CH 2

-N-C-C-N-C-R

1 30 I| ||

OCH

2 O 35 Formula (Ila) wherein WO 2006/079547 PCT/EP2006/000722 -4 Ar is aryl which is unsubstituted or substituted with halo; R 3 is lower alkoxy; and R 1 is methyl. However, neither the U.S. patent No. US 5,378,729 nor the U.S. patent No. 5 US 5,773,475 describe the use of these compounds for treating psychosis, in particular for treating psychosis associated with schizophrenia, in an add on therapy to at least one antipsychotic. WO 02/074297 relates to the use of a compound according to Formula (Ila) 10 wherein Ar is phenyl which may be substituted by at least one halo, R 3 is lower alkoxy containing 1-3 carbon atoms and R 1 is methyl for the preparation of pharmaceutical compositions useful for the treatment of allodynia related to peripheral neuropathic pain. WO 02/074784 relates to the use of a compound having Formula (1a) or/and Formula (Ila) showing antinociceptive properties for treating different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain, e.g. rheumatoid arthritic pain or/and secondary inflammatory osteo-arthritic pain. Psychosis, in particular schizophrenia, is a state of mental impairment 15 marked by following symptoms: - Distorted Perceptions of Reality People with psychosis may have perceptions of reality that are strikingly different from the reality seen and shared by others around them. 20 e Hallucinations and Illusions Hallucinations are perceptions that occur without connection to an appropriate source. Hallucinations can occur in any sensory form - auditory (sound), visual (sight), tactile (touch), gustatory (taste), and olfactory (smell). 25 Auditory hallucinations, particularly the experience of hearing voices that other people do not hear, are a common and often prominent feature of WO 2006/079547 PCT/EP2006/000722 -5 psychosis. - Delusions Delusions are false personal beliefs that are not subject to reason or 5 contradictory evidence and are not explained by a person's usual cultural concepts. * Disordered Thinking Psychosis often affects a person's ability to "think straight." Thoughts may 10 come and go rapidly; the person may not be able to concentrate on one thought for very long and may be easily distracted, unable to focus attention. Disordered thinking is classified largely by its effect on speech and writing. Psychosis is considered to be a symptom of severe mental illness, but not a 15 diagnosis in itself. Although it is not exclusively linked to any particular psychological or physical state, it is particularly associated with schizophrenia, bipolar disorder and severe clinical depression. There are also several physical circumstances that can induce a psychotic state, including electrolyte disorder, urinary tract infections in the elderly, pain 20 syndromes, drug toxicity, and drug withdrawal (especially alcohol, barbiturates, and sometimes benzodiazepines) as well as infections of or injuries to the brain (these psychoses are now more commonly referred to as organic mental disorders). 25 Chronic psychological stress is also known to cause psychotic states, though the exact mechanism is uncertain. Short-lived psychosis triggered by stress is known as brief reactive psychosis. There are also some non-psychiatric conditions which are linked particularly 30 to psychosis, which may include brain tumor, dementia with Lewy bodies, hypoglycemia, intoxication, multiple sclerosis, systemic lupus erythematosus, or/and sarcoidosis.

WO 2006/079547 PCT/EP2006/000722 -6 Psychosis is a common condition in schizophrenia, marked by the typical, above mentioned symptoms. In addition, people with schizophrenia often show "blunted" or "flat" affect. This refers to a severe reduction in emotional expressiveness. 5 Schizophrenia is a chronic, severe, and disabling brain disease found all over the world. Approximately 1 percent of the population develops schizophrenia during their lifetime. The severity of the symptoms and long lasting, chronic pattern of schizophrenia often cause a high degree of 10 disability. People with schizophrenia have a higher rate of suicide than the general population. Approximately 10 percent of people with schizophrenia (especially younger adult males) commit suicide. The first signs of schizophrenia often appear as confusing, or even shocking, changes in behavior. This sudden onset of severe psychotic symptoms is referred to as 15 an "acute" phase of schizophrenia. Some people have only one such psychotic episode; others have many episodes during a lifetime, but lead relatively normal lives during the interim periods. However, the individual with "chronic" schizophrenia, or a 20 continuous or recurring pattern of illness, often does not fully recover normal functioning and typically requires long-term treatment, generally including medication, to control the symptoms. There is no known single cause of schizophrenia. Many diseases, such as 25 heart disease, result from interplay of genetic, behavioral, and other factors; and this may be the case for schizophrenia as well. It has long been known that schizophrenia runs in families. Scientists are studying genetic factors in schizophrenia. It appears likely that multiple genes are involved in creating a predisposition to develop the disorder. In addition, factors such as prenatal 30 difficulties like intrauterine starvation or viral infections, perinatal complications, and various nonspecific stressors, seem to influence the development of schizophrenia. However, it is not yet understood how the genetic predisposition is transmitted, and it cannot yet be accurately WO 2006/079547 PCT/EP2006/000722 -7 predicted whether a given person will or will not develop the disorder. Basic knowledge about brain chemistry and its link to schizophrenia is expanding rapidly. It is likely, although not yet certain, that the disorder is 5 associated with some imbalance of the complex, interrelated chemical systems of the brain, perhaps involving the neurotransmitters dopamine and glutamate. Many studies of people with schizophrenia have found abnormalities in brain 10 structure (for example, enlargement of the fluid-filled cavities, called the ventricles, in the interior of the brain,. and decreased size of certain brain regions) or function (for example, decreased metabolic activity in certain brain regions). It should be emphasized that these abnormalities are quite subtle and are not characteristic of all people with schizophrenia, nor do they 15 occur only in individuals with this illness. Microscopic studies of brain tissue after death have also shown small changes in distribution or number of brain cells in people with schizophrenia. It appears that many (but probably not all) of these changes are present before an individual becomes ill, and schizophrenia may be, in part, a disorder in development of the brain. 20 Available treatments can relieve many symptoms, but most people with schizophrenia continue to suffer some symptoms throughout their lives; it has been estimated that no more than one in five individuals recovers completely. Medications and other treatments for schizophrenia can help 25 reduce and control the distressing symptoms of the illness. However, some people are not greatly helped by available treatments or may prematurely discontinue treatment because of unpleasant side effects. Since schizophrenia may not be a single condition and its causes are not yet known, current treatment methods are based on both clinical research and 30 experience. These approaches are chosen on the basis of their ability to reduce the symptoms of schizophrenia and to lessen the chances that symptoms will return.

WO 2006/079547 PCT/EP2006/000722 -8 Antipsychotic medications have been available since the mid-1950s but they do not "cure" the underlying disease such as schizophrenia or ensure that there will be no further psychotic episodes. Clinically effective antipsychotic agents include tricyclic phenothiazines, thioxanthenes, and dibenzepines, as 5 well as butyrophenones and congeners, other heterocyclics and experimental benzamides. Virtually all of these drugs block D 2 -dopamine receptors and reduce dopamine neurotransmission in forebrain; some of these drugs, in particular the atypical antipsychotics, also interact with D and D 4 -dopaminergic, 5-HT2- and 5-HT 2 -serotonergic and alpha-adrenergic 10 receptors (Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 10t' edition, McGraw-Hill, 2001: Summary of chapter 20 (p. 485)). Antagonism of dopamine-mediated synaptic neurotransmission is an important action of antipsychotic drugs (same document, p. 493, left column, 2 nd para). 15 A number of new antipsychotic agents (the so-called "atypical antipsychotics") have been introduced since 1990. The first of these, clozapine, has been shown to be more effective than other antipsychotics, although the possibility of severe side effects - in particular, a condition 20 called agranulocytosis (loss of the white blood cells that fight infection) requires that patients be monitored with blood tests every one or two weeks. Even newer antipsychotic agents, such as risperidone and olanzapine are safer than the older drugs or clozapine, and they also may be better tolerated. They may or may not treat the illness as well as clozapine, 25 however. Antipsychotic agents are often very effective in treating certain symptoms of schizophrenia, particularly hallucinations and delusions; unfortunately, the drugs may not be as helpful with other symptoms, such; as reduced 30 motivation and emotional expressiveness. Current limitations of antipsychotic agent therapy of psychosis, especially psychosis associated with schizophrenia, include limited efficacy, side WO 2006/079547 PCT/EP2006/000722 -9 effects and delayed onset of action. Valproate was shown to enhance the onset of action of olanzapine or risperidone (Casey et al., Neuropsychopharmacology 28:182ff, 2003). Furthermore, another double blind placebo controlled clinical trial demonstrated that lamotrigine, when 5 added to clozapine, is beneficial for the treatment of treatment-resistant schizophrenia (Tihohen et al., Biol Psychiatr. 54:1241ff, 2003). It is estimated that currently up to 50% of hospitalized schizophrenic patients receive adjunct therapy with anti-epileptic drugs (Citrome L., Psychopharmacology Bull 37(S2):p74ff, 2003) especially for enhancing the 10 onset of action, for controlling the positive symptoms, e.g. hallucinations, the affective symptoms, e.g. depression, as well as the cognitive symptoms, e.g. attention deficit. However, as described in Citrome L., Psychopharmacology Bull 37(S2): 15 p74ff, 2003, data on the use of anticonvulsants for add-on therapy to antipsychotics are inconsistent. Valproate and lamotrigine were shown to preferentially reduce the positive symptoms of schizophrenia (same document, p. 86, last para). A possible locus of action of valproate was said to be direct effects on voltage gated sodium channels (same document, 20 page 78, 2 nd para). However, the use of the anticonvulsant carbamazepine as add-on to the antipsychotic agent haloperidol was associated with a worse clinical outcome compared with antipsychotic monotherapy (same document, page 80, first para). In another study on the use of carbamazepine there was a failure to detect significant improvement on the 25 total BPRS (brief psychiatric rating scale). Adjunctive use of lamotrigine in addition to clozapine resulted in improvement of positive, not negative symptoms of schizophrenia (same document, page 85, 1s para). Reports on the use of other anticonvulsants in schizophrenia report general worsening of psychosis with gabapentin or deterioration in both positive and negative 30 symptoms of schizophrenia with topiramate (same document, page 85, 2 nd para). The reported differences in the efficacy of anticonvulsants as add-on -10 therapeutics to antipsychotics might be due to their. different modes of action. In contrast to antipsychotic agents that share a common antagonistic action on dopamine receptors, current anticonvulsants are believed to work through diverse mechanisms of action. These mechanisms of action are e.g. 5 altering neuronal Impulse propagation via interaction with voltage gated sodium-, calcium-, or potassium channels or affecting neural transmission by either potentiating inhibitory GABA systems or by Inhibition of excitatory glutamate systems. 10 In contrast to current anticonvulsants, lacosamide potentially has a unique but yet unknown molecular mechanism of action. Lacosamide does not directly interact with a variety of known GABA receptor subtypes, nor does it directly Interact with a variety of known glutamate receptor subtypes. In particular, lacosamide does not inhibit voltage-gated sodium or calcium 15 channels and does not potentate potassium currents. In an article by Jann MW, Pharmacotherapy 2004;24(12):1759-1783, which is directed to the cognitive symptoms of schizophrenia, add-on therapy of antipsychotics to several other active agents is described, but no reference 20 is made to add-on therapy of antipsychotics to anticonvulsants. The use of compounds of Formula (Ib) or/and Formula (1Ib) for treatment of psychosis, in particular schizophrenia orland psychosis associated with schizophrenia, in an add-on therapy to at least one antipsychotic agent has 25 not been reported. Thus, the present Invention concerns the use of said compound(s) of Formulae (lb) or/and (1lb) for the preparation of a pharmaceutical composition for the prevention, alleviation or/and treatment of a disease treated with an antipsychotic, in particular psychosis, more particular in the course of schizophrenia, In an add-on therapy to at least 30 one antipsychotic.

C:\NRPonbl\DCC'VXn144147_1 DOC-M7/2011 - 1OA In one aspect, the present invention relates to a use of (R)-2-acetamido-N-benzyl 3-methoxy-propionamide (lacosamide), or of a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the prevention, alleviation or/and treatment of psychosis in an add-on therapy to at least one 5 dopamine antagonist. In another aspect, the present invention relates to a method of preventing, alleviating or/and treating psychosis in an add-on therapy to at least one dopamine antagonist, comprising administering (R)-2-acetamido-N-benzyl-3-methoxy 10 propionamide (lacosamide), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In a further aspect, the present invention relates to a pharmaceutical composition comprising 15 (a) at least one dopamine antagonist, preferably a dopamine D 2 antagonist , and (b) lacosamide in a single dose form. In another aspect, the present invention relates to a pharmaceutical combination 20 comprising two separate dose forms as follows: (a) a first composition comprising at least one dopamine antagonist, and (b) a second composition comprising lacosamide, when used in combination for the prevention, alleviation or/and treatment of psychosis . 25 The application of lacosamide (international non-proprietory name, also formerly called harkoseride or SPM 927) alone had no significant effect on WO 2006/079547 PCT/EP2006/000722 - -11 prepulse inhibition in mice, which is a model of predictive validity for psychosis, particularly for cognitive symptoms. Surprisingly, the compounds (Ib) or/and (I lb), particularly (R)-2-acetamide-N-benzyl-3 methoxypropionamide (lacosamide) potentiated the increase of prepulse 5 inhibition of the antipsychotic agent, clozapine, when administered together. Prepulse inhibition in mice is a model of predictive value for psychosis associated with e.g. schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and alcohol abuse, 10 affective disorders, dyskinesias and related disorders, dementia, mental retardation, polydipsia/hyponatraemia, severe personality disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's syndrom, Parkinson's disease, or/and dopaminergic therapy of Parkinson's disease. 15 Considering the prior art as outlined above, in particular the multitude of modes of action of anticonvulsants, the conflicting results in the add-on therapy of anticonvulsants and antipsychotics, the difference of the mode of action of valproate, the only anticonvulsant with established usefulness in 20 add-on therapy with antipsychotics, as compared to lacosamide, and the lack of mentioning of anticonvulsants in an article on add-on therapy of cognitive symptoms of schizophrenia (Jann MW, see above), a person skilled in the art would not have expected the usefulness of lacosamide in the therapy of psychosis in an add-on therapy to at least one antipsychotic. 25 In a broad sense, the term ,antipsychotic agent" or ,,anti-psychotic" refers to any compound known in the art for prevention, alleviation or treatment of psychosis, including without limitation: (-)-isofloxythepin, (+-)-idazoxan monohydrochioride, (+)-isofloxythepin, 1,2-benzisoxazole-3 30 methanesulfonamide, monosodium salt, 1H-isoindole-a,3(2H)-dione, 2-[4-[4 (1,2-benzisothiazol-3-yl)-1 -piperazinyl]buryl]-hexahydro-, monohydrochloride, (3aR,7aS)-rel-, 2(1 H)-quinolinone, 1-[3-[4-(3 chloropheny)-1-piperazinyl]propyl]-3,4-dihydro-5-methoxy- (OPC 14523), 2- WO 2006/079547 PCT/EP2006/000722 -12 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-[(1 S,2S)-2-carboxycyclopropyl]-m(aS) (LY 341495), abaperidone, acetophenazine, aminosultopride, amisulpride, ampalex, 5 aplindore fumarate, aripiprazole, asenapine maleate, benperidol, benzquinamide, beta-uridine, bromoperidol, buramate, butaperazine, carbadipimidine, carbamazepine, carphenazine, carpipramine, carpipramine dihydrochloride, centbutindole, chlorpenthixol, chlorpromazine, chlorpromazine hydrochloride, chlorprothixene, cis-clopenthixol, cis 10 tramadol, cis-tramadol hydrochloride, citalopram hydrobromide, clocapramine, clocapramine di hydrochloride, clomacran, clopenthixol, clospirazine, clothiapine, clozapine, cyamemazine, devazepide, divalproex sodium, dixyrazine, droperidol, duloxetine hydrochloride, ethyl loflazepate, farampator, fluanisone, flubuperone, fluoxetine hydrochloride, flupentixol, 15 fluphenazine, fluphenazine decanoate, fluphenazine enanthate, fluphenazine hydrochloride, fluspirilene, flutoprazepam, fluvoxamine, fluvoxamine maleate, haloperidol, haloperidol and haloperidol decanoate, iloperidone, isofloxythepin, lamotrigine, loxapine succinate, lurasidone hydrochloride, melperone, melperone hydrochloride, mepazine, 20 mesoridazine, mesoridazine besylate, methoxypromazine, metofenazate, mifepristone, minaprine, minaprine hydrochloride, moclobemide, molindone, molindone hydrochloride, moperone, mosapramine, mosapramine dihydrochloride, neboglamine, nemonapride, ocaperidone, octoclothepine, olanzapine, opipramol, paroxetine, penfluridol, perazine, pericyazine, 25 perimethazine, perospirone, perphenazine, phenothiazines, pimozide, piperacetazine, pipothiazine, pipothiazine palmitate, pipotiazine, pramipexole, prochlorperazine, promazine, prothipendyl, quetiapine, quetiapine fumarate, racemic idazoxan, remoxipride, risperidone, sabcomeline, secretine, sertraline hydrochloride, spiperone, sulforidazine, 30 sulpiride, sultopride, talnetrant, tetrabenazine, thiapride, thiopropazate, thioproperazine, thioridazine, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, thioxanthenes, timeperone, topiramate, trifluoperazine, trifluoperazine hydrochloride, trifluperidol, triflupromazine, WO 2006/079547 PCT/EP2006/000722 -13 zaprasidone, ziprasidone hydrochloride, zonisamide, zotepine, zuclopenthixol acetate, zuclopenthixol decanoate, enantiomers, racemates, pharmaceutically acceptable salts, esters, amides, prodrugs and metabolites thereof. 5 More particularly, term "antipsychotic" or "antipsychotic agent" as used here is meant to comprise classical or so-called typical antipsychotics, also referred to as classical or typical neuroleptics, as well as atypical antipsychotics, also referred to as atypical neuroleptics. Examples for 10 classical antipsychotics are acetophenazine, benperidol, benzquinamide, biriperone, bromoperidol, butaperazine, butyrophenones, carphenazine, centbutindole, chlorpromazine, chlorpromazine hydrochloride, chlorprothixene, clomacran, clopenthixol, clothiapine, cyamemazine, dibenzoxazepines, dihydroindolones, dixyrazine, droperidol, fluanisone, 15 flupentixol, fluphenazine, fluphenazine decanoate, fluphenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decanoate, isofloxythepin, levomepromazine, loxapine succinate, melperone, melperone hydrochloride, mepazine, mesoridazine, mesoridazine besylate, methotrimeprazine, methoxypromazine, metofenazate, molindone, 20 molindone hydrochloride, moperone, neboglamine, nemonapride, octoclothepine, penfluridol, pericyazine, perimethazine, perphenazine, phenothiazines, pimozide, pipamperone, pipothiazine, pipothiazine palmitate, prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine, sultopride, talnetant, thiapride, thiopropazate, thioproperazine, 25 thioridazine, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, thioxanthenes, trifluoperazine, trifluoperazine hydrochloride, trifluperidol, triflupromazine, zuclopenthixol acetate, zuclopenthixol decanoate and enantiomers, racemates, pharmaceutically acceptable salts and derivatives, particularly esters, amides, prodrugs and metabolites 30 thereof. Examples for . atypical antipsychotics are abaperidone, aminosultopride, amisulpride, ampalex, aripiprazole, asenapine maleate, clozapine, fluspirilene, iloperidone, mosapramine, mosapramine dihydrochloride, ocaperidone, olanzapine, oxypertine,. perazine, WO 2006/079547 PCT/EP2006/000722 -14 perospirone, piperacetazine, quetiapine, quetiapine fumarate, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, ziprasidone hydrochloride, zotepine and enantiomers, racemates, pharmaceutically acceptable salts and derivatives, particularly esters, amides, prodrugs and metabolites 5 thereof. The term "antipsychotic" further comprises dopamine antagonists, preferably D 2 antagonists. The term "antipsychotic" or "antipsychotic agent" as used here preferably does not comprise drugs that, although they might also be used in the 10 therapy of psychosis, are no antipsychotics as defined above, such as for example anticonvulsants (such as carbamazepine, valproate, lamotrigine), antidepressants, such as tri- and tetracyclic antidepressants (for example amitryptiline, clomipramine, doxepine, imipramine, trimipramine, nortriptyline, desipramine, maprotiline, trazodone), selective serotonine 15 reuptake inhibitors (for example citaloprame, fluoxetine, fluvoxamine, paroxetine, sertraline), selective noradrenaline-reuptake inhibitors (for example reboxetine), serotonine-noradrenaline-reuptake inhibitors (for example venlafaxine, duloxetine), serotonine-noradrenaline-specific antidepressants (for example mianserine, mirtazapine) or monoamine 20 oxidase inhibitors (for example tranylcypromine, moclobemide), lithium salts or benzodiazepines (for example alprazolame, lorazepame, diazepame). Doses of typical dopamine antagonists which may be employed in the present invention are: Psychosis-treating compound [CAS Mode of action Illustrative dose Reference Ref.] Amisulpride Dopamine D2/D3 200-1200 mg/day http://en.wikipedia.org/ [71675-85-91 antagonist wiki/Amisulpride The recommended starting and target http://www.heaithyplace.com dose is 10 or 15 /C o m m uni t h ought Aripiprazole Dopamine D2 mg/day iCommunities/Thoughto [129722-12-9] partial agonist administered on a Disorders/schizomedication once-a-day S schedule without aripiprazole.asp#DOSAGE regard to meals. Briperone Dopamine [42021-34-1] antagonist 3-4.5 mg/day p.o.

WO 2006/079547 PCT/EP2006/000722 - 15 Psychosis-treating compound [CAS Mode of action Illustrative dose Reference -Ref.) Bromperidol Dopamine D2 3-18 mg/day http://chrom.tutms.tut.ac.jp/ [10457-90-6] antagonist JINNO/DRUGDATA/ . . _ _ e46bromperidol.html Carpipramine [5942-95-0; 7075-03- Dopamine D2 8L antagonist ClocprarineSerotonin Clocapramine antagonist; targets http://chrom.tutms.tut.ac.jp/ [28058-62-0; doit D2 30-150 mg/day JINNO/DRUGDATA/ 47739-98-0] receptor 57clocapramine.html Clorotepine Dopamine [13448-22-11 antagonist Achieve a target dose of 300-450 mg/day by the end of 2 weeks. Adults http://www.rxlist.com/cgi/ Clozapine [5786-21-0] Dopamine -At first, 12.5 mg generiG3/clozapine idshtm antagonist once or twice a http://www.nim~nih.gov/ day. However, the medlineplus/druginfo/uspdi/ dose usually is not 202157.html more than 900 mg a day. lsofloxythepin -- [106819-39-0; Dopamine Psychopharmacology (Berl.) 106819-41-4; antagonist 5 mg/kg orally 1982; 76(4):381-4. 70931-18-91 Melperone 11622-79-3; 3575-80- Dopamine D2 300 mg/day Sumiyoshl: Schizophrenia antagonist Research 62(2):65 Mosapramine [89419-40-9; 98043-60-8] Dopamie D2 6.25-25 mg/day Nemonapride Dopamine D2/D3 [75272-39-8] antagonist 9-36 mg/day Olanzapine Dopamine D2 10 mg/day ht:/ mentalhealth.co J132539-06-11 antagonist httpym/ dr/g/p3-o2.html Penfluridol [26864-56- Dopamine 60-80 mg once J. Clin. Pharmacol., 2] antagonist (D1 and weekly April 1, 1977; 17(4):252 Perospirone.

-

[129273-38-7; Dopamine D2 8-48 mg/day 150915-41-61 antagonist The average Pimozide [2062-784] Dopamine D2 maintenance dose http://home.intekom.com/ antagonist the usual range of pharm/janssen/orap-t.html _____________2 to 12 mg per day WO 2006/079547 PCT/EP2006/000722 -16; Psychosis-treating compound [CAS Mode of action Illustrative dose Reference Ref.] To be administered as an i.m. injection only; it is frequently Pipotiazine palmitate Dopamine possible to achieve http://www.mentalhealth.co [37517-26-3; antagonist; adequate control m/drug/p30 39860-99-6] targets dopamine with a dosage p03.html#Head_8 D2 receptor between 75 and 150 mg administered every 4 weeks Quetiapine fumarate University of Alberta website [111974-69-7; Dopamine D2 Varies called 'DrugBank!; 111974-72-2] antagonist http://www.rxlist.com/cgi/ generic2/guetiap ids.htm#D 6 mg/da http://ajp.psychiatryonline.or ay g/cgi/reprint/1 57/7/1178-a Risperdal Consta: Risperidone Dopamine D2 25-75mg/day i.m. [106266-06-2] antagonist Risperdal Instasolv: http://www.rxlist.com/cgi/ mean modal dose generic/risperidcp.htm#CP 4.1 mg/day 600-800 mg/day Dopamine D2 i.m.; or 200-3200 http://www.mentalhealth.co Suipirde [15676-16-1] antagonist mg/day in 2 or 3 m/drug/p30-s06.htmh divided doses orally Sultopride [53583-79- Dopamine D2 2] antagonist Usual final dose is http:llWww.spisdemo.com/ Tiapride [51012-32-9] Dopamine D2 200-300 mg/day, isae sID antagonist continued for 1-2 =tR 22030204& qsec i months RX22030204&qsSection5 Timiperone Dopamine D2 [57648-21-2] antagonist 4-8 mg/day Ziprasidone Dopamine D2 http://www.geodon.com/ [122883-93-6; antagonist Varies hcp home.asp 146939-27-71 http://www.ukmi.nhs.uk/ Zotepine [26615-21-4] antagist 75-300 mg/day NewMaterial/html/docs/ zotepine.pdf Zuclopenthixol The usual http://www.mentalhealth.co [53772-83-1; 982-24- antagonist therapeutic range m/drug/p30 11 is 20-60mg/day z03.html#Head 8 50-150 mg i.m., repeated if necessary every 2 3 days; maximum http://www.vhpharmsci.com/ Zuclopenthixol Dopamine D2 cumulative dose PDTM/Monographs/ [85721-05-7] antagonist should not exceed zuclopenthixol% 400 mg and 20acetate.htm number of injections should not exceed 4 WO 2006/079547 PCT/EP2006/000722 -17 Psychosis-treating compound [CAS Mode of action Illustrative dose Reference Ref.] The minimum effective dose of Zuclopenthixol Dopamine D2 zuclopenthixo was Pharmacopsychiatry 1994 decnoae opaineD2 200 mg/2 weeks May; 27(3):1 19-1 23 [64053-00-5] antagonist (range 60-400), with a serum concentration of 22 nmol/l (7.1-69.7). 25 In an especially preferred embodiment, the present invention refers to a specific combination of lacosamide with at least one of the antipsychotics as indicated above, more particular with at least one dopamine antagonist, which may be at least one D2 antagonist, even more particular with at least 30 one atypical antipsychotic such as at least one atypical antipsychotic as defined above, most particular clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine. An add-on therapy according to the present invention for the prevention, 35 alleviation or/and treatment of a disease treated with an antipsychotic, in particular psychosis, more particular schizophrenia or/and psychosis associated with schizophrenia, is the co-administration of at least one compound of Formulae (Ib) or/and (lib) with at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, in 40 particular schizophrenia, in order to increase the efficacy, decrease the side effects or/and enhance the onset of action of the antipsychotic medication, for example. The term "co-administration" refers to a plurality of agents that, when 45 administered to a subject together or separately, are co-active in bringing therapeutic benefit to the subject. Such co-administration is also referred to as "combination therapy," "co-therapy," "adjunctive therapy" or "add-on therapy." For example, one agent can potentiate or enhance the therapeutic effect of another, or reduce an adverse side effect of another, or one or more 50 agents can be effectively administered at a lower dose than when used alone, or can provide greater therapeutic benefit than when used alone, or WO 2006/079547 PCT/EP2006/000722 - 18 can complementarily address different aspects, symptoms or etiological factors of a disease or condition. Co-administration comprises administration of the agents in amounts 5 sufficient to achieve or/and maintain therapeutically effective concentrations, e.g. plasma concentrations, in the subject in need thereof. Co-administration comprises simultaneous or/and subsequent administration. Simultaneous administration comprises administration of the agents as a single or as different compositions (see below) "at the same time" within the treatment 10 period. Subsequent administration comprises administration of the agents "at intervals" within the treatment period. Administration "at the same time" includes administration of the at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of 15 psychosis and the compound(s) of Formulae (lb) or/and (l1b) literally "at the same time", but also includes administration directly one after another. Administration "at intervals" includes administration of the at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis and the compound(s) of Formulae (Ib) or/and (l1b) at an interval of 20 1 h at the maximum, preferably 6 h at the maximum, more preferably 12 h at the maximum, even more preferably 1 day at the maximum, and most preferably 1 month at the maximum. The at least one antipsychotic agent useful for the prevention, alleviation 25 or/and treatment of psychosis and the at least one compound of Formulae (lb) or/and (lib) may be formulated in one pharmaceutical preparation (single dose form) for administration at the same time or may be formulated in two distinct preparations (separate dose form) for administration at the same time or at intervals, as described in the preferred embodiments below for 30 example. The two distinct preparations in the separate dose form may be administered by the same route or by different routes. Separate dose forms can optionally be co-packaged, for example in a single WO 2006/079547 PCT/EP2006/000722 -19 container or in a plurality of containers within a single outer package, or co presented in separate packaging ("common presentation"). As an example of co-packaging or common presentation, a kit is contemplated comprising, in separate containers, the at least one antipsychotic and the at least one 5 compound of Formulae (lb) or/and (llb). In another example, the at least one antipsychotic and the at least one compound of Formulae (Ib) or/and (lib) are separately packaged and available for sale independently of one another, but are co-marketed or co-promoted for use according to the invention. The separate dose forms may also be presented to a subject 10 separately and independently, for use according to the invention. Depending on the dosage forms, which may be identical or different, e.g. fast release dosage forms, controlled release dosage forms or/and depot forms, the at least one antipsychotic agent useful for the prevention, 15 alleviation or/and treatment of psychosis and the compound(s) of Formulae (Ib) or/and (lIb) may be administered with the same or with different schedules on a daily, weekly or monthly basis. Therefore, the administration interval of the at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis and the compound(s) of Formulae 20 (lb) or/and (11b) may depend on the administration schedules or/and on the dosage forms. In a preferred embodiment, the compounds of Formulae (lb) or/and (lIb) are used for the preparation of a pharmaceutical composition comprising 25 (a) at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, and (b) at least one compound of Formulae (lb) or/and (llb). In the use of the present invention, the at least one antipsychotic agent 30 useful for the prevention, alleviation or treatment of psychosis may be a dopamine antagonist, preferably a D 2 antagonist, more preferably an atypical antipsychotic agent, even more preferably an atypical antipsychotic as defined above, and most preferably the agent is clozapine, risperidone, WO 2006/079547 PCT/EP2006/000722 -20' aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine. In a further preferred embodiment, the compounds of Formulae (lb) or/and 5 (llb) are used for the preparation of a pharmaceutical composition comprising a single dose form comprising at least one compound according to Formula (ib) or/and Formula (1lb) and at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis in the form of one composition. 10 In another preferred embodiment, the compounds of Formulae (Ib) or/and (lIb) are used for the preparation of a pharmaceutical composition which is a separate dose form comprising (i) a first composition comprising at least one antipsychotic agent useful for 15 the prevention, alleviation or/and treatment of psychosis, and (ii) a second composition comprising at least one compound of Formulae (lb) or/and (lib). In yet another preferred embodiment of the present invention, a 20 commercially available composition of an antipsychotic agent useful for prevention, alleviation or/and treatment of psychosis may be administered to a subject in need thereof. Therefore, in this preferred embodiment, the compounds of Formulae (Ib) or/and (llb) are used for the preparation of a pharmaceutical composition comprising at least one compound according to 25 Formula (lb) or/and Formula (lIb) and not comprising an antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis. The use according to the present invention may comprise the preparation of a pharmaceutical composition for administration of the at least one 30 compound of Formulae (lb) or/and (l1b) and the at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis at the same time or at intervals, as defined above.

WO 2006/079547 PCT/EP2006/000722 -21 A compound according to the invention has the general Formula (lb) R2 5 R-NH-[-C-CNH-]n--C-R1

R

3 10 Formula (lb) wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, heterocyclic, 15 heterocyclic alkyl, alkyl heterocyclic, cycloalkyl or cycloalkyl alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group, and/or at least one electron donating group;

R

1 is hydrogen or alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic alkyl, 20 alkyl heterocyclic, heterocyclic, cycloalkyl, cycloalkyl alkyl, each unsubstituted or substituted with at least one electron donating group and/or at least one electron withdrawing group; and 25

R

2 and R 3 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl alkyl, aryl, halo, heterocyclic, heterocyclic alkyl, alkyl heterocyclic, cycloalkyl, cycloalkyl alkyl, or Z-Y wherein R 2 and R 3 may be unsubstituted or substituted with at least one electron withdrawing group and/or at least one 30 electron donating group; Z is 0, S, S(O)., NR 4 , NR' 6 , PR 4 or a chemical bond; Y is hydrogen, alkyl, aryl, aryl alkyl, alkenyl, alkynyl, halo, heterocyclic, WO 2006/079547 PCT/EP2006/000722 -22 heterocyclic alkyl, alkyl heterocyclic and Y may be unsubstituted or substituted with at least one electron donating group and/or at least -one electron withdrawing group, provided that when Y is halo, Z is a chemical bond, or 5 ZY taken together is NR 4

NRSR

7 , NR 4 ORs, ONR 4

R

7 , OPR 4

R

5 , PR 4

OR

5 ,

SNR

4

R

7 , NR 4

SR

7 , SPR 4 Rs, PR 4

SR

7 , NR 4

PR

5 R, PR 4 NRsR 7 or N*R 5

R

6

R

7 ,

NR

4 C-R5, SCR 5 , NR 4

C-OR

5 , SC-OR 5 , NR4NR-C-ORs 6 ; 10 11 11 11 iI 1 0 0 0 0 %0

R'

6 is hydrogen, alkyl, alkenyl, or alkynyl which may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one 15 electron donating group;

R

4 , R 5 and Ra are independently hydrogen, alkyl, aryl, aryl alkyl, alkenyl, or alkynyl, wherein R 4 , R 5 and Re may independently be unsubstituted or substituted with at least one electron withdrawing group or/and at least one 20 electron donating group;

R

7 is R 6 or COORB or COR 8 , which R 7 may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group; 25

R

8 is hydrogen or alkyl, or aryl alkyl, and the aryl or alkyl group may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group; and 30 n is 1-4; and a is 1-3. Preferably the compound according to the invention has the general Formula (11b) WO 2006/079547 PCT/EP2006/000722 - 23 H H H I I I 5 Ar-CH 2 -- N-C-C-N-C-R O R 3 0 10 Formula (ib) wherein Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one substituent independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamido, 15 aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto, and disulfide;

R

3 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino, and N-alkoxyamino; and 20 R 1 is alkyl. In particular, Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one halo; R 3 is -CH-Q, wherein Q is lower alkoxy; and R 1 is lower alkyl, especially methyl. 25 The present invention is also directed to a pharmaceutical composition comprising at least one compound according to Formula (lb) or/and Formula (lIb) useful for the prevention, alleviation or/and treatment of a disease that can be treated with an antipsychotic, in particular psychosis, in an add-on 30 therapy to at least one antipsychotic agent. In a preferred embodiment, the pharmaceutical composition comprises (a) at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, and 35 (b) at least one compound of Formulae (lb) or/and (Ilb).

WO 2006/079547 PCT/EP2006/000722 -24 In the pharmaceutical composition of the present invention, the at least one antipsychotic agent useful for the prevention, alleviation or treatment of psychosis may be a dopamine antagonist, preferably a D 2 antagonist, more preferably an atypical antipsychotic agent, even more preferably an atypical 5 antipsychotic as defined above, and most preferably the agent is clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine. In a further preferred embodiment, the pharmaceutical composition of the 10 present invention comprises a single dose form comprising at least one compound according to Formula (ib) or/and Formula (lIb) and at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis in the form of one composition. 15 In another preferred embodiment, the pharmaceutical composition of the present invention comprises a separate dose form comprising (i) a first composition comprising at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, and (ii) a second composition comprising at least one compound of Formulae 20 (lb) or/and (Ilb). In yet another preferred embodiment of the present invention, a commercially available composition of an antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis may be administered to 25 a subject in need thereof. Therefore, in this preferred embodiment, the pharmaceutical composition of the present invention comprises at least one compound according to Formula (lb) or/and Formula (ilb) and does not comprise an antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis. 30 The pharmaceutical composition of the present invention may be prepared for administration of the at least one compound of Formulae (Ib) or/and (Ilb) and the at least one antipsychotic agent useful for the prevention, alleviation WO 2006/079547 PCT/EP2006/000722 -25 or/and treatment of psychosis at the same time or at intervals, as defined above. The term "alkyl" (alone or in combination with another term(s)) means a 5 straight- or branched-chain saturated hydrocarbyl substituent preferably containing from 1 to about 20 carbon atoms, more preferably from I to about 8 carbon atoms, and even more preferably from I to about 6 carbon atoms. Most preferably, alkyl is lower alkyl as defined below. 10 The "lower alkyl" groups when used alone or in combination with other groups, are lower alkyl containing from 1 to 6 carbon atoms, especially I to 3 carbon atoms, and may be straight chain or branched. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and isomers of pentyl, hexyl and isomers of hexyl, and the like. 15 The term "alkoxy" (alone or in combination with another term(s)) means an alkylether substituent, i.e., -0-alkyl. The "lower alkoxy" groups are lower alkoxy containing from 1 to 6 carbon 20 atoms, especially 1 to 3 carbon atoms, and may be straight chain or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like. The "aryl alkyl" or "aryl lower alkyl" groups include, for example, benzyl, 25 phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1 diphenylethyl, 1,2-diphenylethyl, and the like. The term "aryl", when used alone or in combination, refers to an aromatic group which contains from 6 up to 18 ring carbon atoms and up to a total of 30 25 carbon atoms and includes the polynuclear aromatics. These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. A polynuclear aromatic compound as used herein, is meant to encompass bicyclic and tricyclic fused aromatic ring systems containing from 10-18 ring WO 2006/079547 PCT/EP2006/000722 -26 carbon atoms and up to a total of 25 carbon atoms. The aryl group includes phenyl, and the polynuclear aromatics e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. The aryl group also includes groups like ferrocenyl. Aryl groups may be unsubstituted or mono or polysubstituted 5 with electron withdrawing or/and electron donating groups as described below. The term "alkenyl" (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more 10 double bonds and preferably from 2 to about 20 carbon atoms, more preferably from 2 to about 8 carbon atoms, and even more preferably from 2 to about 6 carbon atoms, The alkenyl groups, where asymmetric, can have cis or trans configuration. Most preferably, alkenyl is lower alkenyl as defined below. 15 "Lower alkenyl" is an alkenyl group containing from 2 to 6 carbon atoms and at least one double bond. These groups may be straight chained or branched and may be in the Z or E form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2 20 pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1, 3 or 2,4-pentadienyl, and the like. The term "alkynyl" (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more 25 triple bonds and preferably from 2 to about 20 carbon atoms, more preferably from 2 to about 8 carbon atoms, and even more preferably from 2 to about 6 carbon atoms. Most preferably, alkynyl is lower alkynyl as defined below. 30 The term "lower alkynyl" is an alkynyl group containing 2 to 6 carbon atoms and may be straight chained as well as branched. It includes such groups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 pentynyl, 3-pentyny, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.

WO 2006/079547 PCT/EP2006/000722 -27 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. The cycloalkyl groups may be 5 monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. The cycloalkyl may be completely saturated or partially saturated. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl, adamantyl, 10 and the like. Cycloalkyl includes the cis or trans forms. Cycloalkyl groups may be unsubstituted or mono or polysubstituted with electron withdrawing or/and electron donating groups as described below. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems. 15 The terms "electron-withdrawing" and "electron donating" refer to the ability of a substituent to withdraw or donate electrons, respectively, relative to that of hydrogen if the hydrogen atom occupied the same position in the molecule. These terms are well understood by one skilled in the art and are 20 discussed in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York, NY, pp.

16

-

18 (1985) and the discussion therein is incorporated herein by reference. Electron withdrawing groups include halo, including bromo, fluoro, chloro, iodo and the like; nitro, carboxy, alkenyl, alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl such as 25 trifluoromethyl, aryl alkanoyl, carbalkoxy and the like. Electron donating groups include such groups as hydroxy, alkoxy, including methoxy, ethoxy and the like; alkyl, such as methyl, ethyl, and the like; amino, alkylamino, di alkyll) amino, aryloxy such as phenoxy, mercapto, alkylthio, alkylmercapto, disulfide (alkyldithio) and the like. One of ordinary skill in the art will 30 appreciate that some of the aforesaid substituents may be considered to be electron donating or electron withdrawing under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.

WO 2006/079547 PCT/EP2006/000722 -28 "Carbalkoxy" refers to -CO-O-alkyl, wherein alkyl may be lower alkyl as defined above. 5 The term "halo" includes fluoro, chloro, bromo, and iodo. "Alkanoyl" alone or in combination with another term(s) means a straight or branched chain alkanoyl substituent preferably containing from 1 to about 20 carbon atoms, more preferably from 1 to about 8 carbon atoms, even more 10 preferably from 1 to about 6 carbon atoms. The term "acyl" includes lower alkanoyl containing from 1 to 6 carbon atoms and may be straight chains or branched. These groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and 15 isomers of pentanoyl, and hexanoyl and isomers of hexanoyl. As employed herein, a heterocyclic group contains at least one sulfur, nitrogen or oxygen ring atom, but also may include several of said atoms in the ring. The heterocyclic groups contemplated by the present invention 20 include heteroaromatics and saturated and partially saturated heterocyclic compounds. These heterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic and are e.g. fused rings. They may preferably contain up to 18 ring atoms and up to a total of 17 ring carbon atoms and a total of up to 25 carbon atoms. The heterocyclics are also intended to include the so-called 25 benzoheterocyclics. Representative heterocyclics 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, pyrazolindinyl, 30 imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the N-oxides of the nitrogen containing heterocycles, such as the N-oxides of pyridyl, pyrazinyl, and pyrimidinyl and the like.

WO 2006/079547 PCT/EP2006/000722 -29 Heterocyclic groups may be unsubstituted or mono or polysubstituted with electron withdrawing or/and electron donating groups. The preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl, 5 benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a 5 or 6 membered heterocyclic compound. The especially preferred heterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. The most preferred heterocyclics are furyl and pyridyl. 10 The preferred compounds are those wherein n is 1, but di (n=2), tri (n=3) and tetrapeptides (n=4) are also contemplated to be within the scope of the invention. 15 The preferred values of R is aryl lower alkyl, especially benzyl especially those wherein the phenyl ring thereof is unsubstituted or substituted with electron donating groups or/and electron withdrawing groups, such as halo (e.g., F). 20 The preferred R 1 is H or lower alkyl. The most preferred R 1 group is methyl. The preferred electron donating substituents or/and electron withdrawing substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, 25 quaternary ammonium, alkenyl, alkynyl, sulfonium salts, hydroxy, alkoxy, alkyl, amino, alkylamino, di(alkyl)amino, amino alkyl, mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The term "sulfide" encompasses mercapto, mercapto alkyl and alkylthio, while the term disulfide encompasses alkyldithio. Especially preferred electron donating or/and 30 electron withdrawing groups are halo or alkoxy, e.g. lower alkoxy, most preferred are fluoro or methoxy. These preferred substituents may be present on any one of the groups in Formula (lb) or/and (Ilb), e.g. R, R 1 , R 2 ,

R

3 , R 4 , R 5 , R 6 , R' 6 , R 7 , R 8 and/or R 5 o as defined herein.

WO 2006/079547 PCT/EP2006/000722 - 30 The ZY groups representative of R 2 and R 3 include hydroxy, alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino; alkylamino, such as 5 methylamino, ethylamino; arylamino, such as anilino; lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt, hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino (-NH-OH), alkoxy 10 amino [(NHOR 1 3) wherein R 18 is alkyl], N-alkylhydroxyl amino [(NR 1 S)OH wherein R 1 is alkyl], N-alkyl-O-alkylhydroxyamino, i.e., [N(R 18

)OR

1 wherein

R

1 and R 1 are independently alkyl], and 0-hydroxylamino (-O-NH 2 ); alkylamido such as acetamido; trifluoroacetamido; alkoxyamino, (e.g., NH

(OCH

3 ); and heterocyclicamino, such as pyrazoylamino. 15 The preferred heterocyclic groups representative of R 2 and R 3 are monocyclic 5- or 6-membered heterocyclic moieties of the formula: 20 EJ R50 G L 25 (CH), or those corresponding partially or fully saturated form thereof wherein n is 0 or 1; and 30 R 5 o is H or an electron withdrawing group or electron donating group; A, E, L, J and G are independently CH, or a heteroatom selected from the group consisting of N, 0, S; WO 2006/079547 PCT/EP2006/000722 -31 but when n is 0, G is CH, or a heteroatom selected from the group consisting of NH, 0 and S with the proviso that at most two of A, E, L, J and G are heteroatoms. 5 When n is 0, the above heteroaromatic moiety is a five membered ring, while if n is 1, the heterocyclic moiety is a six membered monocyclic heterocyclic moiety. The preferred heterocyclic moieties are those aforementioned heterocyclics which are monocyclic. 10 If the ring depicted hereinabove contains a nitrogen ring atom, then the N oxide forms are also contemplated to be within the scope of the invention. When R 2 or Rs is a heterocyclic 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 additionally 15 be bonded to the main chain by a nitrogen ring atom. Other preferred moieties of R 2 and R 3 are hydrogen, aryl, e.g., phenyl, aryl alkyl, e.g., benzyl and alkyl. 20 It is to be understood that the preferred groups of R 2 and R 3 may be unsubstituted or mono or poly substituted with electron donating or/and electron withdrawing groups. It is preferred that R 2 and R 3 are independently hydrogen, alkyl, which is either unsubstituted or substituted with electron withdrawing groups or/and electron donating groups, such as alkoxy (e.g., 25 methoxy, ethoxy, and the like), N-hydroxylamino, N-alkylhydroxyamino, N alkyl-O-alkyl and alkylhydroxyamino. It is preferred that one of R 2 and R 3 is hydrogen. 30 It is preferred that n is one. It is more preferred that n=1 and one of R 2 and R 3 is hydrogen. It is especially preferred that in this embodiment, R 2 is hydrogen and R 3 is lower WO 2006/079547 PCT/EP2006/000722 -32 alkyl or ZY; Z is 0, NR 4 or PR 4 ; Y is hydrogen or alkyl, e.g. lower alkyl; ZY is NR 4

NR

5

R

7 ,

NR

4

OR

5 , ONR4R 7 , NR 4

C-R

5 or NR 4 C-ORq. 5 || || 0 0 In another especially preferred embodiment, n=1, R 2 is hydrogen and R 3 is alkyl, e.g. lower alkyl which may be substituted or unsubstituted with an 10 electron donating or electron withdrawing group, NR 4 ORs, or ONR4R 7 , In yet another especially preferred embodiment, n = 1, R 2 is hydrogen and

R

3 is alkyl, e.g. lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy, NR 4

OR

5 or ONR 4

R

7 , wherein R 4 , R 5 and R 7 are 15 independently hydrogen or alkyl, R is aryl alkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and R 1 is alkyl, e.g. lower alkyl. In this embodiment it is most preferred that aryl is phenyl, which is unsubstituted or substituted with halo. 20 It is preferred that R 2 is hydrogen and R 3 is hydrogen, an alkyl group which is unsubstituted or substituted by at least an electron donating or electron withdrawing group or ZY. In this preferred embodiment,- it is more preferred that R 3 is hydrogen, an alkyl group such as methyl, which is unsubstituted or substituted by an electron donating group, or NR 4

OR

5 or ONR 4 R, wherein 25 R 4 , Rs and R 7 are independently hydrogen or lower alkyl. It is preferred that the electron donating group is alkoxy, e.g. lower alkoxy, and especially methoxy or ethoxy. It is preferred that R 2 and R 3 are independently hydrogen, alkyl, e.g. lower 30 alkyl, or ZY; Z is 0, NR 4 or PR 4 ; Y is hydrogen or alkyl, e.g. lower alkyl or WO 2006/079547 PCT/EP2006/000722 - 33 ZY is NR 4 RsR 7 , NR 4

OR

5 , ONR 4 R, NR 4 C-Rs or NR 4

C-OR

5 . Il II 0 0 5 It is also preferred that R is aryl alkyl, e.g. aryl lower alkyl. The most preferred aryl for R is phenyl. The most preferred R group is benzyl. In a preferred embodiment, the aryl group may be unsubstituted or substituted with an electron donating or electron withdrawing group. If the aryl ring in R is substituted, it is most preferred that it is substituted with an electron 10 withdrawing group, especially on the aryl ring. The most preferred electron withdrawing group for R is halo, especially fluoro. The preferred R 1 is lower alkyl, especially methyl. 15 It is more preferred that R is aryl lower alkyl and R 1 is lower alkyl. Further preferred compounds are compounds of Formula (lb) wherein n is 1;

R

2 is hydrogen; R 3 is hydrogen, an alkyl group, e.g. a lower alkyl group, especially methyl which is substituted by an electron donating or electron 20 withdrawing group or ZY; R is aryl alkyl, e.g. aryl lower alkyl, such as benzyl, wherein the aryl group is unsubstituted or substituted with an electron donating or electron withdrawing group and R 1 is alkyl, e.g. lower alkyl. In this embodiment, it is more preferred that. R 3 is hydrogen, an alkyl group, e.g. a lower alkyl group, especially methyl, which may be substituted by 25 electron donating group, such as alkoxy, e.g. lower alkoxy, (e.g., methoxy, ethoxy and the like), NR 4

OR

5 or ONR 4

R

7 wherein these groups are defined hereinabove. The most preferred compounds utilized are those of the Formula (llb): 30 H H H I I I Ar-CH 2 -- N-C-C-N-C-R 1 35 OR 3 0 Formula (lib) WO 2006/079547 PCT/EP2006/000722 - 34 wherein Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one electron donating group or electron withdrawing group, especially 5 halo,

R

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

R

3 is as defined herein, but especially hydrogen, alkyl, e.g. lower alkyl, which 10 is unsubstituted or substituted by at least an electron donating group or electron withdrawing group or ZY. It is even more preferred that R 3 is, in this embodiment, hydrogen, an alkyl group which is unsubstituted or substituted by an electron donating group, NR 4

OR

5 or ONR 4

R

7 . It is most preferred that

R

3 is CH 2 -Q, wherein Q is alkoxy, e.g. lower alkoxy, especially containing 1-3 15 carbon atoms; NR 4 ORs or ONR 4

R

7 wherein R 4 is hydrogen or alkyl containing 1-3 carbon atoms, R 5 is hydrogen or alkyl containing 1-3 carbon atoms, and R 7 is hydrogen or alkyl containing 1-3 carbon atoms. The most preferred R 1 is CH 3 . The most preferred R 3 is CH 2 -Q, wherein Q is 20 methoxy. The most preferred aryl is phenyl. The most preferred halo is fluoro. The most preferred compounds include: 25 (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; 30 D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide. It is to be understood that the various combinations and permutations of the WO 2006/079547 PCT/EP2006/000722 - 35 Markush groups of R 1 , R 2 , R 3 , R and n described herein are contemplated to be within the scope of the present invention. Moreover, the present invention also encompasses compounds and compositions which contain one or more elements of each of the Markush groupings in R 1 , R 2 , R 3 , n and R and the 5 various combinations thereof. Thus, for example, the present invention contemplates that R 1 may be one or more of the substituents listed hereinabove in combination with any and all of the substituents of R 2 , R 3 , and R with respect to each value of n. 10 The compounds utilized 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 the D or L form. It is well known in the art that the configuration around a chiral carbon atoms can also be described as R or S in the Cahn-Prelog-Ingold 15 nomenclature system. All of the various configurations around each asymmetric carbon, including the various enantiomers and diastereomers as well as racemic mixtures and mixtures of enantiomers, diastereomers or both are contemplated by the present invention. 20 In the principal chain, there exists asymmetry at the carbon atom to which the groups R 2 and R 3 are attached. When n is 1, the compounds of the present invention is of the formula

R

2 0 25 1 H ||

R-NH-C-C-N-C-R

1 II I O R 3 30 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 previously. As used herein, the term configuration shall refer to the configuration around the carbon atom to which R 2 and R 3 are attached, even though other chiral 35 centers may be present in the molecule. Therefore, when referring to a WO 2006/079547 PCT/EP2006/000722 -36 particular configuration, such as D or L, it is to be understood to mean the D or L stereolsomer at the carbon atom to which R 2 and R 3 are attached. However, it also includes all possible enantiomers and diastereomers at other chiral centers, if any, present in the compound. 5 The compounds of the present invention are directed to all the optical isomers, i.e., the compounds of the present invention are either the L stereoisomer or the D-stereoisomer (at the carbon atom to which R 2 and R 3 are attached). These stereoisomers may be found in mixtures of the L and D 10 stereoisomer, e.g., racemic mixtures. The D stereoisomer is preferred. In lacosamide, the D steroisomer corresponds to the R enantiomer according to the R, S terminology. The compounds of Formulae (lb) or/and (Ilb), in particular lacosamide, may 15 be substantially enantiopure. As used herein, the term "substantially enantiopure" means preferably at least 88%, more preferably at least 90%, most preferably at least 95, 96, 97, 98, or 99% enantiomeric purity. Depending upon the substituents, the present compounds may form addition 20 salts as well. All of these forms are contemplated to be within the scope of this invention including mixtures of the stereoisomeric forms. The manufacture of the utilized compounds is described in U.S. Patent Nos. 5,378,729 and 5,773,475, the contents of both of which are incorporated by 25 reference. The compounds utilized in the present invention are useful as such as depicted in the Formulae (lb) or/and (Ilb) or can be employed in the form of salts in view of its basic nature by the presence of the free amino group. 30 Thus, the compounds of Formulae (Ib) or/and (lIb) form salts with a wide variety of acids, inorganic and organic, including pharmaceutically acceptable acids. The salts with therapeutically acceptable acids are of course useful in the preparation of formulation where enhanced water WO 2006/079547 PCT/EP2006/000722 -37 solubility is most advantageous. These pharmaceutically acceptable salts have also therapeutic efficacy. These salts include salts of inorganic acids such as hydrochloric, hydroiodic, 5 hydrobromic, phosphoric, metaphosphoric, nitric acid and sulfuric acids as well as salts of organic acids, such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, aryl sulfonic, (e.g., p-toluene sulfonic acids, benzenesulfonic), phosphoric, malonic, and the like. 10 The present invention is further directed to a method for the prevention, alleviation or/and treatment of a disease that is treated with an antipsychotic, in particular psychosis, more particular schizophrenia, in an add-on therapy to at least one antipsychotic agent by administration of at least one compound of Formulae (lb) or/and (lIb) to a subject in need thereof. 15 In a preferred embodiment, the method of the present invention comprises (a) the administration of at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, and (b) the administration of at least one compound of Formulae (lb) or/and (lIb) 20 in an add-on therapy in addition to the at least one agent of (a), to a subject in need thereof. In the method of the present invention, the at least one antipsychotic agent useful for the prevention, alleviation or treatment of psychosis may be a 25 dopamine antagonist, preferably a D 2 antagonist, more preferably an atypical antipsychotic agent, even more preferably an atypical antipsychotic as defined above, and most preferably the agent is clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine. 30 It is further preferred that the at least one compound of Formulae (lb) or/and (lb) and the at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis is administered in the form of one WO 2006/079547 PCT/EP2006/000722 - 38 composition (single dose form). In another preferred embodiment, the method of the present invention comprises the administration of a separate dose form comprising 5 (i) a first composition comprising at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, and (ii) a second composition comprising at least one compound of Formulae (Ib) or/and (Ilb). to a subject in need thereof. 10 In yet another preferred embodiment of the present invention, a commercially available composition of an antipsychotic agent useful for prevention, alleviation or/and treatment of psychosis may be administered to a subject in need thereof. Therefore, in this preferred embodiment, the 15 method of the present invention for prevention, alleviation or/and treatment of a disease that is treated with an antipsychotic, in particular psychosis, comprises administration of a pharmaceutical composition comprising at least one compound according to Formula (Ib) or/and Formula (1Ib) and not comprising an antipsychotic agent useful for the prevention, alleviation 20 or/and treatment of psychosis to a subject receiving a commercially available composition containing an antipsychotic agent for prevention, alleviation or/and treatment of psychosis. The compounds according to Formulae (Ib) or/and (lIb) may also be useful 25 in an add-on therapy for disorders or/and diseases other than schizophrenia which are treated by antipsychotic agents. Therefore, yet another subject of the present invention is an add-on therapy for the prevention, alleviation or/and treatment of bipolar disorder, autism, psychosis in diseases other than schizophrenia, e.g. in Alzheimer's disease, or/and attention deficit 30 hyperactivity disorder, by administration of a pharmaceutical composition of the present invention. The compounds according to Formulae (Ib) or/and (11b) may also be used for the preparation of a pharmaceutical composition useful for the prevention, alleviation or/and treatment in an add-on therapy WO 2006/079547 PCT/EP2006/000722 -39 for disorders or/and diseases other than schizophrenia which can be treated by antipsychotic agents, such as bipolar disorder, autism, psychosis in diseases other than schizophrenia, e.g. in Alzheimer's disease, or/and attention deficit hyperactivity disorder. The pharmaceutical composition of 5 the present invention as described herein for treatment of schizophrenia may also be used for the prevention, alleviation or/and treatment in an add on therapy for disorders or/and diseases other than schizophrenia which can be treated by antipsychotic agents, such as bipolar disorder, autism, psychosis in diseases other than schizophrenia, e.g. in Alzheimer's disease, 10 or/and attention deficit hyperactivity disorder. The compounds according to Formulae (lb) or/and (Ilb) may also be useful in an add-on therapy to at least one antipsychotic agent for the treatment of psychosis other than psychosis in schizophrenia. Therefore, yet another 15 subject of the present invention is an add-on therapy to at least one antipsychotic agent for the prevention, alleviation or/and treatment of psychosis associated with e.g. bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and alcohol abuse, affective disorders, dyskinesias and related disorders, dementia, mental retardation, 20 polydipsia/hyponatraemia, severe personality disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's syndrom, Parkinson's disease or/and dopaminergic therapy of Parkinson's disease, by administration of a pharmaceutical composition of the present invention. The compounds 25 according to Formulae (lb) or/and (lib) may also be used for the preparation of a pharmaceutical composition useful for the prevention, alleviation or/and treatment in an add-on therapy to at least one antipsychotic agent for the treatment of psychosis associated with e.g. bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and 30 alcohol abuse, affective disorders, dyskinesias and related disorders, dementia, mental retardation, polydipsia/hyponatraemia, severe personality disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's syndrom, WO 2006/079547 PCT/EP2006/000722 -40 Parkinson's disease or/and dopaminergic therapy of Parkinson's disease. The pharmaceutical composition of the present invention as described herein may also be used for the prevention, alleviation or/and treatment in an add-on therapy for the treatment of psychosis associated with e.g. bipolar 5 disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and alcohol abuse, affective disorders, dyskinesias and related disorders, dementia, mental retardation, polydipsia/hyponatraemia, severe personality disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's 10 syndrom, Parkinson's disease, or/and dopaminergic therapy of Parkinson's disease. It is preferred that the compound utilized in the present invention is used in therapeutically effective amounts. 15 The physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the patient under treatment, the age of the patient, the type of malady being treated. He 20 will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached. When the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given 25 parenterally. The compounds are useful in the same manner as comparable therapeutic agents and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents. Typical doses of antipsychotic agents administered to a subject in need 30 thereof in the add-on therapy to at least one antipsychotic agent of the present invention are the doses of the dopamine antagonists as given above or are the following doses: olanzapine 5-20 mg/day, clozapine 100-900 mg/day, quetiapine 100-800 mg/day, risperidone 1-16 mg/day, aripiprazole WO 2006/079547 PCT/EP2006/000722 -41 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 may also be included in the pharmaceutical composition of the present invention, or/and may be used for the preparation of a pharmaceutical composition of 5 the present invention. The physician is able to determine the administration route of the at least one agent useful for the prevention, alleviation or/and treatment of psychosis, which may be the same or different to the administration route of 10 the at least one compound of the present invention of Formulae (Ib) or/and (11b). Typical administration routes of the at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis are oral, intravenous, intramuscular, intrathecal or subcutaneous routes. Oral or/and intravenous administration is preferred. 15 In a preferred embodiment, the compounds of Formulae (lb) or/and (11b) of the present invention are administered in amounts ranging from about I mg to about 10 mg per kilogram of body weight per day. This dosage regimen may be adjusted by the physician to provide the optimum therapeutic 20 response. Patients in need thereof may be treated with doses of the compound of the present invention of at least 50 mg/day, preferably of at least 100 mg, more preferably at least 200 mg/day, even more preferably of at least 300 mg/day and most preferably of at least 400 mg/day. Generally, a patient in need thereof may be treated with doses at a maximum of 6 g/day, 25 more preferably a maximum of I g/day and most preferably a maximum of 600 mg/day. In some cases, however, higher or lower doses may be needed. In another preferred embodiment, the daily doses are increased until a 30 predetermined daily dose is reached which is maintained during the further treatment. In yet another preferred embodiment, several divided doses may be WO 2006/079547 PCT/EP2006/000722 -42 administered daily. For example, three doses per day may be administered, preferably two doses per day. It is more preferred to administer a single dose per day. 5 In yet another preferred embodiment, an amount of the compounds of the present invention may be administered which results in a plasma concentration of 0.1 to 15 pg/mI (trough) and 5 to 18.5 pg/ml (peak), calculated as an average over a plurality of treated subjects. 10 The compounds of Formulae (Ib) or/and (Ilb) may be administered in a convenient manner, such as by oral, intravenous (where water soluble), intramuscular, intrathecal or subcutaneous routes. Oral or/and i.v. administration is preferred. 15 The pharmaceutical composition of the present invention may be prepared for the treatment regimen as described above, in particular for the treatment with doses as described above, to effect plasma concentrations as described above, for administration periods or/and administration routes as specified in the embodiments of the present invention as described above. 20 The pharmaceutical compositions of the present invention comprising the at least one antipsychotic agent for the prevention, alleviation or/and treatment of psychosis, in particular schizophrenia, is formulated with common carriers, diluents or/and -auxiliary substances known to a person skilled in 25 the art. In the case of a separate dose form, the first composition comprising at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis and the second composition comprising at least one compound of Formulae (lb) or/and (lIb) may comprise carriers, diluents or/and auxiliary substances which are independently from each other, 30 identical or different in the first composition comprising at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis and the second composition comprising at least one compound of Formulae (lb) or/and (lib).

WO 2006/079547 PCT/EP2006/000722 -43 The compounds of Formulae (lb) or/and (lib) may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed 5 into tablets, or it may be incorporated directly into the food or the diet. For oral therapeutic administration, the active compound of Formulae (lb) or/and (lib) may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at 10 least 1% of active compound of Formulae (Ib) or/and (11b). The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit. The amount of active compound of Formulae (lb) or/and (lIb) in such therapeutically useful compositions is such that a suitable dosage will be 15 obtained. Preferred compositions or preparations according to the present invention contains between about 10 mg and 6 g active compound of Formulae (lb) or/and (11b). The tablets, troches, pills, capsules and the like may also contain the 20 following: A binder such as gum tragacanth, acacia, 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 such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of 25 wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may 30 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 WO 2006/079547 PCT/EP2006/000722 -44 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 contemplated wherein the active 5 ingredient is bound to an ion exchange resin which, optionally, can be coated with a diffusion barrier coating to modify the release properties of the resin. The active compound may also be administered parenterally or 10 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. 15 The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where 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. It must be stable under the conditions of manufacture 20 and storage and must be preserved 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, and vegetable oils. The proper fluidity can be 25 maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the 30 like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

WO 2006/079547 PCT/EP2006/000722 -45 Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered 5 sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum 10 drying the freeze-drying technique plus any additional desired ingredient from previously sterile-filtered solution thereof. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agent, 15 isotonic and absorption delaying agents for pharmaceutical active substances as well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. 20 It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a 25 predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifics for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material an the particular therapeutic effect to be achieved, and (b) the 30 limitations inherent in the art of compounding such as active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

WO 2006/079547 PCT/EP2006/000722 -46 The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore described. A unit dosage form can, for example, contain the principal active compound in 5 amounts ranging from about 10 mg to about 6 g. Expressed in proportions, the active compound is generally present in the carrier in an amount from about 1 to about 750 mg/mI of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. 10 As used herein the term "patient" or "subject" refers to a warm blooded animal, and preferably mammals, such as, for example, cats, dogs, horses, cows, pigs, mice, rats and primates, including humans. The preferred patient is a human. 15 The term "treat" refers to preventing, curing or alleviating the patient's disease or condition. The compounds of the present invention are administered to a patient 20 suffering from the aforementioned type of disorder in an effective amount. These amounts are equivalent to the therapeutically effective amounts described hereinabove. The following example shows the properties of lacosamide, formerly called 25 Harkoseride, or SPM 927, potentiating the prepulse inhibition of the antipsychotic agent clozapine in mice when administered together. The used substance was lacosamide. The standard chemical nomenclature is (R)-2-acetamide-N-benzyl-3-methoxypropionamide. 30 Example The effects of lacosamide alone and in combination with clozapine in an animal model for schizophrenia.

WO 2006/079547 PCT/EP2006/000722 -47 Some anticonvulsants have proven pre-clinical and/or clinical efficacy as add-on therapy to antipsychotics for schizophrenia. Lacosamide was tested in a simple animal model with predictive validity for psychosos such as 5 schizophrenia (i.e. prepulse inhibition (PPI) of the acoustic startle reflex). Lacosamide was tested alone and in combination with the atypical antipsychotic agent clozapine. It should be noted that prepulse inhibition is a general model of psychosis 10 and therefore indicative for psychosis associated with other diseases or conditions, such as psychosis associated with schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug or/and alcohol abuse, affective disorders, dyskinesias and related disorders, dementia, mental retardation, polydipsia/hyponatraemia, severe 15 personality disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's syndrom, Parkinson's disease, or/and dopaminergic therapy of Parkinson's disease. 20 The acoustic startle is an unconditioned reflex response to an external auditory stimulation. PPI refers to the reduction in the startle response caused by the presentation of a low-intensity auditory stimulus prior to the startle stimulus. The PPI paradigm is the choice for the study of schizophrenia and antipsychotic action due to the similarities between the 25 results from human and rodent studies. Antipsychotic agents, such as clozapine, result in a dose-dependent increase in PPI in mice. Thus, an increase of PPI in normal mice may be indicative of antipsychotic efficacy. C57BL/6J mice obtained from the Jackson Laboratory, Bar Harbor, Maine 30 were received at the age of 6 weeks and were assigned unique identification numbers (tail marked). Animals were housed 4 per cage in polycarbonate cages with filter tops and acclimated for 7 days. All animals were examined, handled, and weighed prior to initiation of the study to assure adequate WO 2006/079547 PCT/EP2006/000722 -48 health and suitability and to minimize non-specific stress associated with manipulation. During the course of the study, 12/12 light/dark cycles and a room 5 temperature of 20 to 230C were maintained with a relative humidity maintained around 50%. Chow and water were provided ad libitum for the duration of the study. Each mouse was randomly assigned across the treatment groups and balanced by cage numbers. The test was performed during the animal's light cycle phase. Twelve animals were used in each 10 treatment group. Lacosamide was dissolved in Saline (0.9% NaCl in sterile H 2 0). Clozapine was dissolved in 1% Tween 80 in sterile H 2 0 at a final pH of 6.0. All compounds were administered intraperitoneal (ip) (volume injection: 10 15 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 administered saline (vehicle 1, VEH 1) or 1% Tween 80 (vehicle 2, VEH 2) at a pH of 6.0. The drug treatments were balanced across days and the animals only used once. All tests were conducted blind. All 20 compounds were administered 30 min prior to testing. Animals were placed in the PPI chambers (Med Associates) for a 5 min session of white noise (70 dB) habituation. After the acclimation period the test session was automatically started. The session started with an 25 habituation block of 6 presentations of the startle stimulus alone, followed by 10 PPI blocks of 6 different types of trials. Trial types are: null (no stimuli), startle (120 dB), startle plus prepulse (4, 8 and 12 dB over background noise i.e. 74, 78 or 82 dB) and prepulse alone (82 dB). Trial types were presented at random within each block. Each trial started with a 50 ms null period 30 during which baseline movements are recorded. There was a subsequent 20 ms period during which prepulse stimuli were presented and responses to the prepulse measured. After further 100 ms the startle stimuli were presented for 40 ms and responses recorded for 100 ms from startle onset.

WO 2006/079547 PCT/EP2006/000722 -49 Responses were sampled every ms. The inter-trial interval was variable with an average of 15 s (range from 10 to 20 s). In startle alone trials the basic auditory startle is measured and in prepulse plus startle trials the amount of inhibition of the normal startle is determined and expressed as a percentage 5 of the basic startle response (from startle alone trials), excluding the startle response of the first habituation block. Eight animals were tested at one time. Twelve animals were tested in each group. A total of 108 mice were tested 10 using following design: VEHI/VEH2 lacosamide [3 mg/kg] / VEH2 lacosamide [10 mg/kg] / VEH2 15 lacosamide [30 mg/kg] / VEH2 VEH1 / 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] 20 A two-way ANOVA (analysis of variance) with treatments as independent factor and pre-pulse intensities as dependent factor (i.e. repeated measure) was performed. This was followed by the post-hoc Newman Keuls test where indicated. A p < 0.05 was considered significant. The Newman Keuls 25 test allows for the comparison of two independent samples. Animals injected with clozapine (3 mg/kg) showed a significant improvement in prepulse inhibition in comparison to animals receiving vehicle (p<0.05, table 1). When administered alone, lacosamide did not have any significant 30 effect on prepulse inhibition at any dose tested, when compared to vehicle. The administration of lacosamide (at 30 mg/kg but not at 3 or 10 mg/kg) in combination with clozapine however, did potentiate the effect of clozapine alone on prepulse inhibition i.e. the prepulse inhibition was significantly WO 2006/079547 PCT/EP2006/000722 -50 higher than the effect of clozapine alone (p<0.05). The data obtained provide a basis for clinical trials in humans using lacosamide as an add-on therapy for the treatment of psychosis, in particular 5 of schizophrenia or psychosis associated with schizophrenia or/and other diseases or conditions. Table I Effects of lacosamide alone and in combination with clozapine on prepulse 10 inhibition of the acoustic startle response (PPI) Treatment Mean PPI VEH 1NEH 2 29±3 VEH 1/CLOZ [3 mg/kg] 45±2* lacosamide [3 mg/kg]NEH 2 29±3 lacosamide [10 mg/kg]NEH 2 34±3 lacosamide [30 mglkg]NEH 2 27±2 lacosamide [3 mg/kg]/ CLOZ [3 43±2* mg/kg] lacosamide [10 mg/kg]/ CLOZ [3 45±2* mg/kg] lacosamide [30 mg/kg]! CLOZ [3 57±5*,# mg/kg] 15 -51 * p<0.05 for comparison to VEHNEH group # p<0.05 for comparison to VEH/CLOZ group Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (23)

1. Use of (R)-2-acetamido-N-benzyl-3-methoxy-propionamide (lacosamide), or of a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the prevention, alleviation or/and treatment of psychosis in an add-on therapy to at least one dopamine antagonist.

2. Use according to claim 1, wherein the psychosis is associated with schizophrenia, bipolar disorder, autism, Alzheimer's disease, or/and attention deficit hyperactivity disorder, drug or/and alcohol abuse, affective disorders, dyskinesias, dementia, mental retardation, polydipsia/hyponatraemia, severe personality disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's syndrome, Parkinson's disease or/and dopaminergic therapy of Parkinson's disease.

3. Use according to claim 1 or 2, wherein the psychosis is associated with schizophrenia.

4. Use according to any one of claims 1-3, wherein the compound is (R)-2 acetamido-N-benzyl-3-methoxypropionamide (lacosamide).

5. Use according to any one of claims 1-4, wherein the pharmaceutical composition is prepared for treatment with doses of the compound as defined in claims 1 or 4 of at least of 100 mg/day.

6. Use according to any one of claims 1-5, wherein the pharmaceutical composition is prepared for treatment with doses of the compound defined in claims 1 or 4 of at least of 200 mg/day.

7. Use according to any one of claims 1-6, wherein the pharmaceutical composition is prepared for treatment with doses of the compound of claims 1 or 4 at a maximum of 1 g/day, and most preferably at a maximum of 600 mg/day. - 53

8. Use according to any one of claims 1-7, wherein the pharmaceutical composition is prepared for treatment with the compound of claims 1 or 4 with increasing daily doses until a predetermined daily dose is reached which is maintained during the further treatment.

9. Use according to any one of claims 1-8, wherein the pharmaceutical composition is prepared for the treatment with lacosamide in two doses per day or in a single dose per day.

10. Use according to any one of claims 1-9, wherein the pharmaceutical composition is prepared for an administration resulting in a plasma concentration of lacosamide of 0.1 to 15 pg/ml (trough) and 5 to 18.5 pg/ml (peak), calculated as an average over a plurality of treated subjects.

11. Use according to any one of claims 1-10, wherein the pharmaceutical composition is prepared for oral or i.v. administration.

12. Use according to any one of claims 1-11, wherein the at least one dopamine antagonist and lacosamide are formulated in one pharmaceutical preparation (single dose form).

13. Use according to any one of claims 1-11, wherein the pharmaceutical composition is a combination preparation comprising two separate compositions as follows: (a) a first composition comprising at least one dopamine antagonist, and (b) a second composition comprising lacosamide.

14. Use according to any one of claims 1-13, wherein the dopamine antagonist is a D 2 antagonist.

15. Use according to claim 14, wherein the D 2 antagonist is an atypical antipsychotic agent. - 54

16. Use according to claim 14, wherein the D 2 antagonist is selected from abaperidone, aminosultopride, amisulpride, ampalex, aripiprazole, asenapine maleate, clozapine, fluspirilene, iloperidone, mosapramine, mosapramine dihydrochloride, ocaperidone, olanzapine, oxypertine, perazine, perospirone, piperacetazine, quetiapine, quetiapine fumarate, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, ziprasidone hydrochloride or/and zotepine, most preferably clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine.

17. Use according to claim 4 wherein the dopamine antagonist is olanzapine applied in a dose of 5-20 mg/day, clozapine in a dose of 100-900 mg/day, quetiapine in a dose of 100-800 mg/day, risperidone in a dose of 1-16 mg/day, aripiprazole in a dose of 3-30 mg/day, ziprasidone in a dose of 40-160 mg/day, sulpiride in a dose of 300-1600 mg/day, amisulpride in a dose of 50-1200 mg/day, or/and zotepine in a dose of 75-450 mg/day.

18. Use according to any one of claims 1-17, wherein the dopamine agonist is clozapine.

19. A pharmaceutical composition comprising (a) at least one dopamine antagonist, preferably a dopamine D 2 antagonist , and (b) lacosamide in a single dose form.

20 A pharmaceutical combination comprising two separate dose forms as follows: (a) a first composition comprising at least one dopamine antagonist, and (b) a second composition comprising lacosamide, when used in combination for the prevention, alleviation or/and treatment of psychosis . -55

21. The pharmaceutical composition according to claim 19 or the pharmaceutical combination according to claim 20, wherein the at least one dopamine antagonist is a D 2 antagonist, more preferably an atypical antipsychotic agent, even more preferably abaperidone, aminosultopride, amisulpride, ampalex, aripiprazole, asenapine maleate, clozapine, fluspirilene, iloperidone, mosapramine, mosapramine dihydrochloride, ocaperidone, olanzapine, oxypertine, perazine, perospirone, piperacetazine, quetiapine, quetiapine fumarate, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, ziprasidone hydrochloride or/and zotepine, most preferably clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine.

22.A method of preventing, alleviating or/and treating psychosis in an add-on therapy to at least one dopamine antagonist, comprising administering (R)-2 acetamido-N-benzyl-3-methoxy-propionamide (lacosamide), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

23. Use according to claim 1, the pharmaceutical composition according to claim 19, the pharmaceutical combination according to claim 20, or a method according to claim 22, substantially as hereinbefore described with reference to any one of the examples.