WO2006079547A2 - Lacosamide pour traitement d'appoint - Google Patents

Lacosamide pour traitement d'appoint Download PDF

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Publication number
WO2006079547A2
WO2006079547A2 PCT/EP2006/000722 EP2006000722W WO2006079547A2 WO 2006079547 A2 WO2006079547 A2 WO 2006079547A2 EP 2006000722 W EP2006000722 W EP 2006000722W WO 2006079547 A2 WO2006079547 A2 WO 2006079547A2
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Prior art keywords
alkyl
use according
aryl
unsubstituted
day
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PCT/EP2006/000722
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English (en)
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WO2006079547A3 (fr
Inventor
Thomas STÖHR
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Schwarz Pharma Ag
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Priority claimed from EP05001843A external-priority patent/EP1688137A1/fr
Priority to MX2007009070A priority Critical patent/MX2007009070A/es
Priority to JP2007552583A priority patent/JP2008528532A/ja
Priority to EP06706448A priority patent/EP1841417A2/fr
Priority to CA002595330A priority patent/CA2595330A1/fr
Priority to AU2006208630A priority patent/AU2006208630B2/en
Application filed by Schwarz Pharma Ag filed Critical Schwarz Pharma Ag
Priority to EA200701594A priority patent/EA015566B1/ru
Priority to BRPI0607043-4A priority patent/BRPI0607043A2/pt
Publication of WO2006079547A2 publication Critical patent/WO2006079547A2/fr
Publication of WO2006079547A3 publication Critical patent/WO2006079547A3/fr
Priority to IL183973A priority patent/IL183973A0/en
Priority to NO20074361A priority patent/NO20074361L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • the present invention is directed to the use of a class of peptide compounds for the prevention, alleviation or/and treatment of schizophrenia, 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 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.
  • 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):
  • 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 substituted with at least one electron withdrawing group or electron donating group;
  • Ri is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group;
  • R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower 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 O, S, S(O) 3 , NR 4 , PR 4 or a chemical bond
  • 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 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 or PR 4 SR 7 , NR 4 PR 5 R 6 or PR 4 NR 5 R 7 ,
  • R 4 , R 5 and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5 and R 6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and
  • R 7 is R 6 or COOR 8 or COR 8 ;
  • Re 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;
  • U.S. Patent No. 5,773,475 also discloses additional compounds useful for treating CNS disorders. These compounds are N-benzyl-2-amino-3- methoxy-propionamide having the Formula (Ha):
  • WO 02/074297 relates to the use of a compound according to Formula (Ha) wherein Ar is phenyl which may be substituted by at least one halo, R 3 is lower alkoxy containing 1-3 carbon atoms and Ri 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 (Ia) or/and Formula (Ha) 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.
  • 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 marked by following symptoms:
  • 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). Auditory hallucinations, particularly the experience of hearing voices that other people do not hear, are a common and often prominent feature of psychosis.
  • Delusions are false personal beliefs that are not subject to reason or contradictory evidence and are not explained by a person's usual cultural concepts.
  • Psychosis is considered to be a symptom of severe mental illness, but not a 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 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).
  • Psychosis is a common condition in schizophrenia, marked by the typical, above mentioned symptoms.
  • people with schizophrenia often show "blunted” or “fiat” affect. This refers to a severe reduction in emotional expressiveness.
  • 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 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 an "acute" phase of schizophrenia.
  • Clinically effective antipsychotic agents include tricyclic phenothiazines, thioxanthenes, and dibenzepines, as 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 Dr and D 4 -dopaminergic, 5-H ⁇ 2A- and 5-HT 2 c-serotonergic and alpha-adrenergic receptors (Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 10 th 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).
  • clozapine 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 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, 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 motivation and emotional expressiveness.
  • lacosamide 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 channels and does not potentiate potassium currents.
  • the use of compounds of Formula (Ib) or/and Formula (lib) for treatment of psychosis, in particular schizophrenia or/and psychosis associated with schizophrenia, in an add-on therapy to at least one antipsychotic agent has not been reported.
  • the present invention concerns the use of said compound(s) of Formulae (Ib) or/and (lib) 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 one antipsychotic.
  • 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, 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.
  • psychosis associated with e.g. 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 disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's Disease, Tourette's syndrom,
  • ..antipsychotic agent or ..antipsychotic refers to any compound known in the art for prevention, alleviation or treatment of psychosis, including without limitation: (-)-isofloxythepin, (+-)-idazoxan monohydrochloride, (+)-isofloxythepin, 1 ,2-benzisoxazole-3- 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(1H)-quinolinone, 1-[3-[4-(3- chlorophenyl)-1-piperazinyl]propyl]-3,4-dihydro-5-methoxy- (OPC 14523
  • 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 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, flupentixol, fluphenazine, fluphenazine decanoate, fluphenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decanoate, isofloxythepin, levomepromazine, loxapine succinate, melperone, melperone hydrochloride, mepazine, mes
  • Examples for atypical antipsychotics are abaperidone, aminosultopride, amisulpride, ampalex, aripiprazole, asenapine maleate, clozapine, fluspirilene, iloperidone, mosapramine, mosapramine dihydrochloride, ocaperidone, olanzapine, oxypertine, .
  • antipsychotic further comprises dopamine antagonists, preferably D 2 antagonists.
  • antipsychotic or "antipsychotic agent” as used here preferably does not comprise drugs that, although they might also be used in the 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- 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
  • Doses of typical dopamine antagonists which may be employed in the present invention are:
  • 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 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.
  • dopamine antagonist which may be at least one D2 antagonist
  • at least 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, 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 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.
  • co-administration refers to a plurality of agents that, when 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.”
  • one agent can potentiate or enhance the therapeutic effect of another, or reduce an adverse side effect of another, or one or more agents can be effectively administered at a lower dose than when used alone, or can provide greater therapeutic benefit than when used alone, or can complementarity address different aspects, symptoms or etiological factors of a disease or condition.
  • Co-administration comprises administration of the agents in amounts 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 period.
  • Subsequent administration comprises administration of the agents
  • Administration "at the same time” 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 (lib) 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 (lib) at an interval of 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.
  • (Ib) 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 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 coritainer or in a plurality of containers within a single outer package, or co- presented in separate packaging ("common presentation").
  • a kit is contemplated comprising, in separate containers, the at least one antipsychotic and the at least one compound of Formulae (Ib) or/and (lib).
  • 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 separately and independently, for use according to the invention.
  • 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 (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 (Ib) or/and (lib) may depend on the administration schedules or/and on the dosage forms.
  • the compounds of Formulae (Ib) or/and (lib) are used for the preparation of a pharmaceutical composition comprising (a) at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, and (b) at least one compound of Formulae (Ib) or/and (lib).
  • 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 antipsychotic as defined above, and most preferably the agent is clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine.
  • the compounds of Formulae (Ib) or/and (lib) 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 (lib) and at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis in the form of one composition.
  • a first composition comprising at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis, and
  • 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 compounds of Formulae (Ib) or/and (lib) are used for the preparation of a pharmaceutical composition comprising at least one compound according to Formula (Ib) 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 compound of Formulae (Ib) or/and (lib) 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.
  • a compound according to the invention has the general Formula (Ib)
  • R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, heterocyclic, 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;
  • Ri is hydrogen or alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic alkyl, 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;
  • 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 electron donating group;
  • Z is O, S, S(O) 3 , NR 4 , NR'e, PR 4 or a chemical bond;
  • Y is hydrogen, alkyl, aryl, aryl alkyl, alkenyl, alkynyl, halo, heterocyclic, 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
  • ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 , PR 4 SR 7 , NR 4 PR 5 R 6 , PR 4 NR 5 R 7 Or N + R 5 R 6 R 7 ,
  • R'e is hydrogen, alkyl, alkenyl, or alkynyl which may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group;
  • R 4 , R 5 and R 6 are independently hydrogen, alkyl, aryl, aryl alkyl, alkenyl, or alkynyl, wherein R 4 , R 5 and R 6 may independently be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group;
  • R 7 is R 6 or COOR 8 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;
  • 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;
  • the compound according to the invention has the general Formula (lib) H H H Ar-CHr-N I-C-C I-N I-C-Ri O Il R I 3 O Il
  • 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, 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 R 1 is alkyl.
  • Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one halo;
  • R 3 is -CH 2 -Q, wherein Q is lower alkoxy; and
  • Ri is lower alkyl, especially methyl.
  • the present invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to Formula (Ib) 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 therapy to at least one antipsychotic agent.
  • the pharmaceutical composition comprises
  • the at least one antipsychotic agent useful for the prevention, alleviation or/and 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, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine.
  • the pharmaceutical composition of the 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.
  • 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 (Ib) or/and (lib).
  • a commercially available composition of an antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis may be administered to 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 (Ib) or/and Formula (lib) and does not comprise an antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis.
  • the pharmaceutical composition of the present invention may be prepared for administration of the at least one compound of Formulae (Ib) or/and (lib) 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.
  • alkyi (alone or in combination with another term(s)) means a straight- or branched-chain saturated hydrocarbyl substituent preferably containing from 1 to about 20 carbon atoms, more preferably from 1 to about 8 carbon atoms, and even more preferably from 1 to about 6 carbon atoms. Most preferably, alkyl is lower alkyl as defined below.
  • lower alkyl groups when used alone or in combination with other groups, are lower alkyl containing from 1 to 6 carbon atoms, especially 1 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.
  • alkoxy (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl.
  • lower alkoxy groups are lower alkoxy containing from 1 to 6 carbon 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.
  • aryl alkyl or “aryl lower alkyl” groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1- diphenylethyl, 1 ,2-diphenylethyl, and the like.
  • 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 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 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 with electron withdrawing or/and electron donating groups as described below.
  • alkenyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more 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.
  • “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- pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1 , 3 or 2,4-pentadienyl, and the like.
  • alkynyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more 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.
  • 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-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.
  • 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 monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused.
  • the cycloalkyl may be completely saturated or partially saturated.
  • 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.
  • electrospraying 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 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 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 (alkyl) amino, aryloxy such as phenoxy, mercapto, alkylthio, alkylmercapto, disulfide (alkyldithio) and the like.
  • alkyl such as methyl, ethyl, and the like
  • substituents may be considered to be electron donating or electron withdrawing under different chemical conditions.
  • the present invention contemplates any combination of substituents selected from the above-identified groups.
  • Carbalkoxy refers to -CO-O-alkyl,
  • 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 preferably from 1 to about 6 carbon atoms.
  • 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 isomers of pentanoyl, and hexanoyl and isomers of hexanoyl.
  • 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 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 benzoheterocyclics.
  • 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, imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl
  • the preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl, 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.
  • n 1
  • 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).
  • halo e.g., F
  • the preferred Ri is H or lower alkyl.
  • the most preferred Ri 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, quaternary ammonium, alkenyl, alkynyl, sulfonium salts, hydroxy, alkoxy, alkyl, amino, alkylamino, di(alkyl)amino, amino alkyl, mercapto, mercaptoalkyl, alkylthio, and alkyldithio.
  • sulfide encompasses mercapto, mercapto alkyl and alkylthio, while the term disulfide encompasses alkyldithio.
  • Especially preferred electron donating or/and 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 (Ib) or/and (lib), e.g. R, Ri, R 2 , R 3 , RA, RS, Re, R'e, R7, Rs and/or R 50 as defined herein.
  • 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 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 amino [(NHORi 8 ) wherein R 18 is
  • the preferred heterocyclic groups representative of R 2 and R 3 are monocyclic 5- or 6-membered heterocyclic moieties of the formula:
  • n 0 or 1 ;
  • R 50 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, O, S; but when n is 0, G is CH 1 or a heteroatom selected from the group consisting of NH, O and S with the proviso that at most two of A, E, L, J and G are heteroatoms.
  • 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.
  • 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.
  • R 2 or R 3 When R 2 or R 3 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 be bonded to the main chain by a nitrogen ring atom.
  • R 2 and R 3 are hydrogen, aryl, e.g., phenyl, aryl alkyl, e.g., benzyl and alkyl.
  • 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., methoxy, ethoxy, and the like), N-hydroxylamino, N-alkylhydroxyamino, N- alkyl-O-alkyl and alkylhydroxyamino.
  • alkoxy e.g., methoxy, ethoxy, and the like
  • R 2 and R 3 are hydrogen.
  • n is one.
  • Z is O, NR 4 or PR 4 ; Y is hydrogen or alkyl, e.g. lower alkyl; ZY is NR 4 NR 5 R?,
  • n 1
  • R 2 is hydrogen and R 3 is alkyl, e.g. lower alkyl which may be substituted or unsubstituted with an electron donating or electron withdrawing group, NR 4 OR 5 , or ONR 4 R 7 ,
  • 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 independently hydrogen or alkyl, R is aryl alkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and Ri is alkyl, e.g. lower alkyl. In this embodiment it is most preferred that aryl is phenyl, which is unsubstituted or substituted with halo.
  • 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.
  • 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 7 , wherein R 4 , R 5 and R 7 are independently hydrogen or lower alkyl.
  • the electron donating group is alkoxy, e.g. lower alkoxy, and especially methoxy or ethoxy.
  • R 2 and R 3 are independently hydrogen, alkyl, e.g. lower alkyl, or ZY;
  • Z is O, NR 4 or PR 4 ;
  • Y is hydrogen or alkyl, e.g. lower alkyl or ZY is NR 4 R 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , NR 4 C-R 5 or NR 4 C-OR 5 .
  • R is aryl alkyl, e.g. aryl lower alkyl.
  • the most preferred aryl for R is phenyl.
  • the most preferred R group is benzyl.
  • 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 withdrawing group, especially on the aryl ring.
  • the most preferred electron withdrawing group for R is halo, especially fluoro.
  • the preferred Ri is lower alkyl, especially methyl.
  • R is aryl lower alkyl and Ri is lower alkyl.
  • 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 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
  • Ri is alkyl, e.g. lower alkyl.
  • R 3 is hydrogen, an alkyl group, e.g.
  • a lower alkyl group especially methyl, which may be substituted by 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.
  • Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one electron donating group or electron withdrawing group, especially halo,
  • Ri is alkyl, especially containing 1-3 carbon atoms
  • R 3 is as defined herein, but especially hydrogen, alkyl, e.g. lower alkyl, which 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 ONR4R7. It is most preferred that
  • R 3 is CH 2 -Q 1 wherein Q is alkoxy, e.g. lower alkoxy, especially containing 1-3 carbon atoms; NR 4 OR 5 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 Ri is CH 3 .
  • the most preferred R 3 is CH 2 -Q, wherein Q is methoxy.
  • the most preferred aryl is phenyl.
  • the most preferred halo is fluoro.
  • the most preferred compounds include: (R)-2-acetamido-N-benzyl-3-methoxy-propionamide;
  • 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-lngold 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.
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , Re, R'e, R?, Rs, Rso Z and Y are as defined previously.
  • 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 centers may be present in the molecule. Therefore, when referring to a particular configuration, such as D or L, it is to be understood to mean the D or L stereoisomer at the carbon atom to which R 2 and R 3 are attached. However, it also includes all possible enantiomers and diastereomers at other chira! centers, if any, present in the compound.
  • 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 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 (Ib) or/and (lib), in particular lacosamide, may be substantially enantiopure.
  • substantially enantiopure means preferably at least 88%, more preferably at least 90%, most preferably at least 95, 96, 97, 98, or 99% enantiomeric purity.
  • the present compounds may form addition salts as well. All of these forms are contemplated to be within the scope of this invention including mixtures of the stereoisomeric forms.
  • the compounds utilized in the present invention are useful as such as depicted in the Formulae (Ib) or/and (lib) or can be employed in the form of salts in view of its basic nature by the presence of the free amino group.
  • 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 solubility is most advantageous.
  • These pharmaceutically acceptable salts have also therapeutic efficacy.
  • These salts include salts of inorganic acids such as hydrochloric, hydroiodic, 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.
  • inorganic acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid and sulfuric acids
  • organic acids such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, aryl sulfonic, (e.g., p-to
  • 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 (Ib) or/and (lib) to a subject in need thereof.
  • the method of the present invention comprises
  • 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 antipsychotic as defined above, and most preferably the agent is clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride or/and zotepine.
  • the at least one compound of Formulae (Ib) or/and (lib) and the at least one antipsychotic agent useful for the prevention, alleviation or/and treatment of psychosis is administered in the form of one composition (single dose form).
  • the method of the present invention comprises the administration of 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
  • 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 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 (lib) and not comprising an antipsychotic agent useful for the prevention, alleviation 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.
  • a pharmaceutical composition comprising at least one compound according to Formula (Ib) or/and Formula (lib) and not comprising an antipsychotic agent useful for the prevention, alleviation 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 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 hyperactivity disorder, by administration of a pharmaceutical composition of the present invention.
  • the compounds according to Formulae (Ib) 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 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.
  • 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 the present invention as described herein for treatment of schizophrenia may also be used for the prevention, alleviation or/and treatment in an addon 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, or/and attention deficit hyperactivity disorder.
  • the compounds according to Formulae (Ib) or/and (lib) 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 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, 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 according to Formulae (Ib) 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 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, Parkinson's disease or/and dopaminergic therapy of Parkinson's disease.
  • 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, polydipsia/hyponatraemia, severe personality disorder
  • 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 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 syndrom, Parkinson's disease, or/and dopaminergic therapy of Parkinson's disease.
  • 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, polydipsia/hyponatraemia, severe personality disorder, acute episodes of mania, obsessive compulsive disorder, intractable chronic insomnia
  • the compound utilized in the present invention is used in therapeutically effective amounts.
  • 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 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 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 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 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 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 the at least one compound of the present invention of Formulae (Ib) or/and (lib).
  • 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.
  • the compounds of Formulae (Ib) or/and (lib) of the present invention are administered in amounts ranging from about 1 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 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.
  • a patient in need thereof may be treated with doses at a maximum of 6 g/day, more preferably a maximum of 1 g/day and most preferably a maximum of 600 mg/day. In some cases, however, higher or lower doses may be needed.
  • the daily doses are increased until a predetermined daily dose is reached which is maintained during the further treatment.
  • several divided doses may be administered daily.
  • three doses per day may be administered, preferably two doses per day. It is more preferred to administer a single dose per day.
  • an amount of the compounds of the present invention may be administered which results in a plasma concentration of 0.1 to 15 ⁇ g/ml (trough) and 5 to 18.5 ⁇ g/ml (peak), calculated as an average over a plurality of treated subjects.
  • the compounds of Formulae (Ib) or/and (lib) 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.
  • 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.
  • 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 the art.
  • 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 (Ib) or/and (lib) may comprise carriers, diluents or/and auxiliary substances which are independently from each other, 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 (Ib) or/and (lib).
  • the compounds of Formulae (Ib) or/and (Mb) 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 into tablets, or it may be incorporated directly into the food or the diet.
  • the active compound of Formulae (Ib) 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 least 1% of active compound of Formulae (Ib) or/and (lib).
  • compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit.
  • amount of active compound of Formulae (Ib) or/and (lib) in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention contains between about 10 mg and 6 g active compound of Formulae (Ib) or/and (lib).
  • the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, com 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 wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, com 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
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermin
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • sustained release dosage forms are contemplated wherein the active 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 intraperitoneal ⁇ .
  • 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.
  • 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.
  • 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 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 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 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.
  • 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 sterilization.
  • 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.
  • the preferred methods of preparation are vacuum drying the freeze-drying technique plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agent, 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.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a 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 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.
  • 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 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/ml of carrier.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • patient refers to a warm blooded animal, and preferably mammals, such as, for example, cats, dogs, horses, cows, pigs, mice, rats and primates, including humans.
  • mammals such as, for example, cats, dogs, horses, cows, pigs, mice, rats and primates, including humans.
  • the preferred patient is a human.
  • treat refers to preventing, curing or alleviating the patient's disease or condition.
  • the compounds of the present invention are administered to a patient suffering from the aforementioned type of disorder in an effective amount. These amounts are equivalent to the therapeutically effective amounts described hereinabove.
  • the following example shows the properties of lacosamide, formerly called 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.
  • prepulse inhibition is a general model of psychosis 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 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.
  • 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 results from human and rodent studies.
  • Antipsychotic agents such as clozapine, result in a dose-dependent increase in PPI in mice.
  • an increase of PPI in normal mice may be indicative of antipsychotic efficacy.
  • mice obtained from the Jackson Laboratory, Bar Harbor, Maine 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 health and suitability and to minimize non-specific stress associated with manipulation.
  • Lacosamide was dissolved in Saline (0.9% NaCI in sterile H 2 O).
  • Clozapine was dissolved in 1% Tween 80 in sterile H 2 O at a final pH of 6.0. All compounds were administered intraperitoneal (ip) (volume injection: 10 ml/kg). Lacosamide was administered at doses of 1, 10 and 30 mg/kg and Clozapine at a dose of 3 mg/kg. Doses are expressed as mg of salt.
  • Control mice were 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 compounds were administered 30 min prior to testing.
  • mice 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 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 during which baseline movements are recorded.
  • mice Twelve animals were tested in each group. A total of 108 mice were tested using following design:
  • VEH1/VEH2 lacosamide [3 mg/kg] / VEH2 lacosamide [10 mg/kg] / VEH2 lacosamide [30 mg/kg] / VEH2
  • 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 of schizophrenia or psychosis associated with schizophrenia or/and other diseases or conditions.

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Abstract

La présente invention concerne l'utilisation d'une classe de composés peptidiques pour la prévention, le soulagement et/ou le traitement d'une maladie qui est traitée à l'aide d'antipsychotiques, en particulier la psychose, plus particulièrement la schizophrénie, dans un traitement d'appoint d'au moins un antipsychotique.
PCT/EP2006/000722 2005-01-28 2006-01-27 Lacosamide pour traitement d'appoint WO2006079547A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BRPI0607043-4A BRPI0607043A2 (pt) 2005-01-28 2006-01-27 lacosamida para terapia de adição
JP2007552583A JP2008528532A (ja) 2005-01-28 2006-01-27 統合失調症のアドオン治療用ｓｐｍ９２７
EP06706448A EP1841417A2 (fr) 2005-01-28 2006-01-27 Spm 927 pour la thérapie adjuvante de la schizophrenie
CA002595330A CA2595330A1 (fr) 2005-01-28 2006-01-27 Lacosamide pour traitement d'appoint
AU2006208630A AU2006208630B2 (en) 2005-01-28 2006-01-27 SPM 927 for add-on therapy of schizophrenia
MX2007009070A MX2007009070A (es) 2005-01-28 2006-01-27 (spm 927) para terapia supletoria de esquizofrenia.
EA200701594A EA015566B1 (ru) 2005-01-28 2006-01-27 Применение пептидного соединения для добавочной терапии к антагонисту дофамина и фармацевтическая композиция, его содержащая
IL183973A IL183973A0 (en) 2005-01-28 2007-06-14 Spm 927 for add -on therapy of schizophrenia
NO20074361A NO20074361L (no) 2005-01-28 2007-08-27 Lacosamid for "add-on"-terapi

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US64741005P 2005-01-28 2005-01-28
US60/647,410 2005-01-28
EP05001843.1 2005-01-28
EP05001843A EP1688137A1 (fr) 2005-01-28 2005-01-28 SPM 927 pour la thérapie adjuvante de la schizophrenie

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WO2008000513A3 (fr) * 2006-06-30 2008-09-04 Sanol Arznei Schwarz Gmbh Composés peptidiques pour le traitement de troubles liés à l'hyperexcitabilité et de maladies associées à un dysfonctionnement d'un canal ionique
WO2007144195A3 (fr) * 2006-06-15 2008-09-04 Sanol Arznei Schwarz Gmbh Composition pharmaceutique ayant un effet anticonvulsivant synergique
WO2009053070A1 (fr) 2007-10-23 2009-04-30 Schwarz Pharma Ag Composés pour le traitement de conditions de démyélinisation
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WO2012072256A2 (fr) 2010-12-02 2012-06-07 Ucb Pharma Gmbh Formulation de lacosamide en prise quotidienne unique
EP2468261A1 (fr) 2010-12-02 2012-06-27 UCB Pharma GmbH Formulation de lacosamide
EP2035029B1 (fr) 2006-06-15 2016-11-30 UCB Pharma GmbH Composés peptidiques destinés au traitement de l'état de mal épileptique réfractaire
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11278634B1 (en) 2021-02-12 2022-03-22 Extrovis Ag Stable parenteral composition of lacosamide
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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US9095557B2 (en) 2006-06-15 2015-08-04 Ucb Pharma Gmbh Anticonvulsant combination therapy
WO2007144195A3 (fr) * 2006-06-15 2008-09-04 Sanol Arznei Schwarz Gmbh Composition pharmaceutique ayant un effet anticonvulsivant synergique
US9446011B2 (en) 2006-06-15 2016-09-20 Ucb Pharma Gmbh Anticonvulsant combination therapy
EP2992891B1 (fr) 2006-06-15 2020-08-05 UCB Pharma GmbH Composition pharmaceutique comprenant brivaracetam et lacosamide ayant un effet anticonvulsivant synergique
EP2035029B1 (fr) 2006-06-15 2016-11-30 UCB Pharma GmbH Composés peptidiques destinés au traitement de l'état de mal épileptique réfractaire
EA027836B1 (ru) * 2006-06-15 2017-09-29 ЮСиБи ФАРМА ГМБХ Фармацевтическая комбинация для профилактики, облегчения и/или лечения приступов эпилепсии и ее применение
AU2007260207B2 (en) * 2006-06-15 2012-11-08 Ucb Pharma Gmbh Pharmaceutical composition with synergistic anticonvulsant effect
EA019757B1 (ru) * 2006-06-15 2014-06-30 ЮСиБи ФАРМА ГМБХ Фармацевтическая композиция с синергетическим противосудорожным эффектом
WO2008000513A3 (fr) * 2006-06-30 2008-09-04 Sanol Arznei Schwarz Gmbh Composés peptidiques pour le traitement de troubles liés à l'hyperexcitabilité et de maladies associées à un dysfonctionnement d'un canal ionique
US9308183B2 (en) 2006-06-30 2016-04-12 Ucb Pharma Gmbh Therapy for hyperexcitability disorders
EP1920780A1 (fr) * 2006-10-12 2008-05-14 Schwarz Pharma Ag Composés peptidiques pour le traitement des maladies liées à l'hyperexcitabilité
WO2009053070A1 (fr) 2007-10-23 2009-04-30 Schwarz Pharma Ag Composés pour le traitement de conditions de démyélinisation
WO2010077916A1 (fr) * 2008-12-16 2010-07-08 Eurand, Inc. Compositions comportant de la melpèrone
WO2012072256A2 (fr) 2010-12-02 2012-06-07 Ucb Pharma Gmbh Formulation de lacosamide en prise quotidienne unique
WO2012084126A2 (fr) 2010-12-02 2012-06-28 Ucb Pharma Gmbh Formulation de lacosamide
US10149818B2 (en) 2010-12-02 2018-12-11 Ucb Pharma Gmbh Daily formulation of lacosamide
EP2468261A1 (fr) 2010-12-02 2012-06-27 UCB Pharma GmbH Formulation de lacosamide
EP3766485A1 (fr) 2010-12-02 2021-01-20 UCB Pharma GmbH Formulation de lacosamide à prise quotidienne unique
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11370753B2 (en) 2017-12-05 2022-06-28 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10660875B1 (en) 2017-12-05 2020-05-26 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10577317B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10874639B2 (en) 2017-12-05 2020-12-29 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11767293B2 (en) 2017-12-05 2023-09-26 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11517558B2 (en) 2017-12-05 2022-12-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10800738B2 (en) 2017-12-05 2020-10-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11654113B2 (en) 2019-06-04 2023-05-23 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11278634B1 (en) 2021-02-12 2022-03-22 Extrovis Ag Stable parenteral composition of lacosamide

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IL183973A0 (en) 2008-12-29
AU2006208630B2 (en) 2011-09-29
AU2006208630A1 (en) 2006-08-03
NO20074361L (no) 2007-10-26
EA200701594A1 (ru) 2008-02-28
KR20070096058A (ko) 2007-10-01
AR057643A1 (es) 2007-12-12
CA2595330A1 (fr) 2006-08-03
BRPI0607043A2 (pt) 2009-08-04
MX2007009070A (es) 2007-09-12

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