WO2012168411A1 - Use of carpipramine in the treatment of psychiatric and developmental disorders in children and adolescents - Google Patents

Use of carpipramine in the treatment of psychiatric and developmental disorders in children and adolescents Download PDF

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WO2012168411A1
WO2012168411A1 PCT/EP2012/060866 EP2012060866W WO2012168411A1 WO 2012168411 A1 WO2012168411 A1 WO 2012168411A1 EP 2012060866 W EP2012060866 W EP 2012060866W WO 2012168411 A1 WO2012168411 A1 WO 2012168411A1
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carpipramine
disorders
patients
pharmaceutical compositions
patients diagnosed
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French (fr)
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Pierre Sokoloff
Lucilla Mansuy
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Pierre Fabre Medicament
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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

Definitions

  • carpipramine from both anti-depressants and anti-depressants.
  • the indications for carpipramine come together around a common denominator: functional deficits of activity and mood, which are at the forefront in the deficit evolution of psychoses, in neurotic asthenia, autistic withdrawal, or who frequently follow drug withdrawal treatment (Deniker P, Ginestet D, Lôo H (1975) Psychotropic Drugs and Mechanisms of Mood Regulation.)
  • Carpipramine has also been used in children and adolescents to treat pediatric psychoses, including autistic elements (Tridon P and Mises R (1978) Carpipramine in Child Psychiatry, Brain, 4: 587-594; Danjoux J, Moron P (1979) The effect of an inhibition- counteracting agent in the teenager. Neuropsychiatric. Teenage childhood. 27 (6): 293-297).
  • the clinical data of these old studies in children and adolescents showed a heterogeneity of the therapeutic response, in studied cases themselves heterogeneous in their nosographic characterization, nowadays obsolete compared to current nosographic classifications.
  • the effectiveness evaluations were descriptive in nature, and did not meet the current effectiveness criteria based on validated rating scales.
  • autism atypical mood disorders.
  • carpipramine is known to antagonize serotonin 5-HT2 receptors (Sechter D, and Lôo H (1990) 5 HT2 antagonists and carpipramine, Rev. Prat 40 (25): 2363-2365), and as a D2 receptor antagonist.
  • Carpipramine is also an antagonist of alphal and alpha2 adrenergic receptors (Setoguchi M, Sakamori M, Takehara S, Fukuda T (1985) Effects of iminodibenzyl antipsychotic drugs on brain dopamine and alpha-adrenergic receptors, Eur J. Pharmacol 112 (3). ): 313-322).
  • Alpha2 adrenergic receptors which play a critical role in the regulation of neuronal activity and release of neurotransmitters (Ruffolo RR Jr, AJ Nichols, Stadel JM, Hieble JP (1993) Pharmacology and therapeutic applications of alpha2-adrenoceptor subtypes. Annu Rev. Pharmacol Toxicol 33: 243-79), consist of three genetically and functionally distinct subtypes: alpha2A, alpha2B and alpha2C.
  • the alpha2A subtype is the most abundant of the 3 subtypes and is widely distributed throughout the body, including the brain where it is present in particular on noradrenergic neurons to control the release of norepinephrine.
  • the presence of the alpha2B subtype is restricted to the thalamus and very limited in level of expression, compared to that of peripheral organs such as the kidney.
  • the distribution of the alpha2C receptor in the central nervous system is mainly found in areas such as the olfactory tubercle, the striatum and the hippocampus, the locus coeruleus and other brain regions containing the cellular bodies of noradrenergic neurons, and in the dopaminergic centers of the midbrain, such as the black substance and the ventral tegmental zone.
  • Alpha2 adrenergic receptors modulate central nervous system functions, such as sympathetic tone, alertness, attention, and responsiveness to a stress environment.
  • central nervous system functions such as sympathetic tone, alertness, attention, and responsiveness to a stress environment.
  • pharmacological probes for alpha2 adrenergic receptor subtypes a vision of their roles has come from the development and use of genetically modified mice, either by inactivation, targeted mutation or overexpression of their genes.
  • alpha2A subtype is the main mediator of most of the effects induced by non-selective subtype alpha2 adrenergic agonists, such as sedation, analgesia, hypothermia, sympathetic inhibition and reduction of arterial pressure.
  • the alpha2C subtype is expressed in the areas that are involved in memory and other cognitive functions, engaged by fronto-striato- thalamic feedback loops.
  • Over-expressing alpha2C transgenic mice perform poorly in the spatial or non-spatial memory tests of the "Morris pool" (Morris R (1984) Developments of ater-maze procedure for studying spatial learning in the rat J. Neurosci, Methods 11 (1): 47-60), treatment with a nonselective alpha2 antagonist of a subtype restores a normal phenotype in these mice. It has therefore been proposed that selective antagonists of the alpha2C subtype could modulate the operation of the fronto-striato-thalamic feedback loop more efficiently than alpha2C non-selective alpha2 antagonists.
  • non-preferential alpha2 antagonists of a subtype such as dexefaroxan
  • acetylcholine norepinephrine
  • cortical dopamine acetylcholine
  • norepinephrine norepinephrine
  • cortical dopamine acetylcholine
  • Rosenquist AC Rosenquist AC (2004) Noradrenergic mechanisms in neurodegenerative diseases: Brain Res., Brain Res Rev. 45 (1): 38-78.
  • a specific contribution of the alpha2C subtype in these effects remained to be demonstrated experimentally, in particular with a specific pharmacological probe.
  • the inventors have re-evaluated the pharmacology of carpipramine with respect to different receptor subtypes for the neuromediators noradrenaline, dopamine and serotonin. Unexpectedly, they found that the receptors for which carpipramine had the most affinity were the subtypes of alpha2B and alpha2C noradrenergic receptors (Example 1). Given the presumed role of the alpha2C subtype described above, they conclude that carpipramine derives its clinical activity from its particular activity for the alpha2C subtype.
  • carpipramine has a pharmacological profile very similar to that of F17334 with respect to changes in the metabolites of norepinephrine, dopamine and serotonin, especially in the limbic regions (Example 3);
  • carpipramine because of these preferential blocking properties of the alpha2C subtype, has a procognitive and anti-stress activity that can improve learning.
  • the present invention therefore relates to a selection of patients and their treatment with carpipramine, according to criteria relating to the property of carpipramine preferentially block the alpha2C subtype, which can serve, on the one hand, to characterize patients who can benefit from treatment with carpipramine, and to exclude those with disorders that can not be improved with carpipramine.
  • treatment means preventing or inhibiting the onset or progression, or reversing the progression of the condition to which the term applies, or one or more symptoms of this condition.
  • the term patient refers to a human of an age between 3 and 30 years likely to be affected by a psychiatric or neuro-developmental disorder.
  • the diseases belong to the spectrum of psychiatric disorders or pervasive developmental disorders of the child and adolescent previously stated, patients are selected according to whether they have learning disorders or of socialization.
  • patients treated with carpipramine have cognitive behavior and motivation disorders, in relation to communication and contact with others, but also the different areas of acquisition and social behavior.
  • the invention relates to the possibility of improving or compensating for cognitive impairment in the various functions that underlie social relations, imaginative activities, the expression of emotions, cognitive, perceptual or motor skills.
  • the global disorder of the modalities of relationship of the young subject with others and the surrounding world is accompanied by behavioral difficulties, common to the pathologies of the psychotic and non-psychotic sphere of the developmental type and which can thus be specified in a dimensional approach:
  • cognition and learning correspond to the management of the processes of information processing, acquisition and representation of knowledge, beliefs, problem solving and action planning
  • the inventors postulate that treatment with disinhibitory properties with respect to stress and acting on attention and motivation abilities, may have a beneficial effect only in patients who have a deficit of social cognition, but also a weakening or even a abolition of executive functions and "central coherence" (Weak central coherence) in the aforementioned clinical situations.
  • carpipramine Thanks to its previously unknown alpha2C pharmacological activity, carpipramine possesses clinical properties and original indications that can provide a therapeutic response, notably by promoting "neurotic remodeling" in asthenia, activity reductions, 1 hyperemotivity, hypovigilance associated with psychotic and developmental disorders in children and adolescents.
  • the efficacy of carpipramine treatment is improved over its previous clinical use without the selection of patients.
  • patients treated with carpipramine had a broad and heterogeneous spectrum of symptoms including those unrelated to dysfunction that could be improved by blocking the alpha2C subtype, which explains the variable therapeutic response observed then.
  • patients who are excluded for treatment with carpipramine are those suffering from delusional, hallucinatory, aggressive and self-injurious disorders, for whom other treatments exist, for example by risperidone (Risperdal ⁇ ).
  • carpipramine is used in these clinical situations, in the form of a pharmaceutically acceptable salt selected from the inorganic acid addition salts non-toxic for the patient to whom they are administered.
  • pharmaceutically acceptable refers to molecular entities and compositions that produce no adverse, allergic or other adverse reactions when administered to an animal or human.
  • Examples of pharmaceutically acceptable acid addition salts include bromohydrate, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate salts, and the like. (See, for example, S. M. Berge, et al., (1977) "Pharmaceutical Salts," J. Pharm Sci., 66: 1-19).
  • Carpipramine is administered either alone or in pharmaceutical compositions which may include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient includes any diluent, adjuvant or excipient, such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or else agents which provide change the absorption and intestinal and digestive resorption.
  • preservatives such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or else agents which provide change the absorption and intestinal and digestive resorption.
  • fillers such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or else agents which provide change the absorption and intestinal and digestive resorption.
  • disintegrating such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or else agents which
  • compositions containing carpipramine according to the invention can be administered orally, parenterally, nasally or rectally.
  • carpipramine will be administered orally in an appropriate formulation.
  • Formulations suitable for oral administration to a patient include therapeutic units such as capsules, cachets or tablets, each containing a predetermined amount of carpipramine; they also include a powder or granules; or a solution or suspension in an aqueous liquid or a non-aqueous liquid; or an oil / water or water / oil liquid emulsion. More preferably, these pharmaceutical compositions will be particularly suitable for children and adolescents and will be in the form of an emulsion or an oral solution, in the form of syrup or solution to be diluted in a glass of water.
  • Dosages of the pharmaceutical compositions containing carpipramine in the compositions of the invention are adjusted to obtain an amount of active substance that is effective in achieving the desired therapeutic response for a particular composition in the method of administration.
  • the chosen level of dosage therefore depends on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors. It is adjusted according to the age and weight of the patient.
  • the carpipramine is administered in pharmaceutically acceptable compositions wherein the daily dose of carpipramine, expressed as base, is between 5 to 200 mg, taken in one or more times per day.
  • the daily dose of carpipramine, expressed as base is between 5 to 200 mg, taken in one or more times per day.
  • Carpipramine was evaluated in a series of radioactive ligand binding assays to recombinant human receptor and receptor subtypes, expressed by cultured cell membranes.
  • the methods employed have been described in Ne man-Tancredi A, Assie MB, Martel JC, Cosi C, Slot LB, Palm C, Rauly-Lestienne I, Colpaert F, Vacher B, Cussac D (2007) F15063, a potential antipsychotic ith D2 / D3 antagonist, 5-HT1A agonist and D4 partial agonist properties.
  • I In vitro receptor affinity and efficacy profile. Br. J. Pharmacol. 151 (2): 237-252.
  • the inhibition constant (Ki) for each of the receptors has been measured and is reported in the following table:
  • This Figure 1 shows the inhibition of [3H] RX821002 binding to cell membranes expressing the alpha2A, alpha2B and alpha2C receptor subtypes by increasing concentrations of carpipramine.
  • the radioligand was used at concentrations of 2 nM, 10 nM and 4 nM for alpha 2A, 2B and 2C receptors, respectively.
  • Example 2
  • F17334 (3- (((2R, 11bS) -9-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a] isoquinolin-2-yl) methyl) imidazolidine-2,4-dione), was used as a prototype of a selective alpha2C subtype antagonist.
  • F17334 is an antagonist of alpha2A, alpha2B and alpha2C receptor subtypes, with the following affinities:
  • F17334 or carpipramine increases the metabolite levels of noradrenaline (normetanephrine, NMN) and dopamine (homovanillic acid, HVA), but not or very little that of serotonin (5-hydroxyindole acetic acid, 5-HIAA ) ex vivo dosed in the prefrontal cortex and limbic regions (olfactory tubercle + nucleus accumbens + septum) of the mouse 1 hour after administration in increasing single doses ( Figure 2).
  • Figure 2 shows changes in tissue levels of normetanephrine (NMN) and homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the prefrontal cortex (PFC) and limbic regions (tubercle). olfactory + nucleus accumbens + septum, Limbic) under the influence of treatment with F17334 or carpipramine administered in increasing single doses.
  • the levels in the treated groups are expressed as a percentage of a saline solution (0.9% NaCl) injected into a group of control mice.
  • METHODS Levels of normetanephrine (NMN) and 3-methoxytyramine (3-MT) in extracts of brain structures obtained from rodents sacrificed in high power microwaves were validated as markers of release, respectively.
  • noradrenaline and dopamine Wood, PL and Altar, CA: Dopamine release in vivo from nigrostriatal, mesolimbic, and mesocortical neurons: utility of 3-methoxytyramine measurements, Pharmacologi cal Rev. 40, 163- 187, 1988; Wood, PL , Kim, H.
  • the passive avoidance test consists of teaching a rat not to enter a dark compartment (its natural place of preference) where it has previously received an electric shock (0.8 mA).
  • Reluctance of the animal (the lapse of time, or "latency", to enter the dark compartment), measured 48 hours after his training, is considered as an index of his explicit-declarative memory. Latency increases with the intensity of the training shock.
  • a shock of 0.8 raA strongly decreases the latency (increases the "memory"), while a weak shock (0.1 mA) has no significant effect.
  • Figure 3 shows F17334, administered at the indicated doses, which increases the latency to enter a compartment associated with electric shock. * P ⁇ 0.05; ** P ⁇ 00.1 versus control animals.
  • the apparatus consists of a clear compartment (30 X 30 X 30 cm) connected to an opening (7 X 7 cm) to a dark compartment (20 X 20 X 12 cm), equipped with a metal grid floor.
  • a lamp 60 W
  • the rat is placed in the bright and light compartment, which it can explore for 30 sec.
  • the entrance of the dark compartment is then open and when the rat has put its 4 legs in this compartment, the door connecting the 2 compartments is closed and the rat receives a low intensity electric shock (0.1 mA for 2 sec).
  • a low intensity electric shock 0.1 mA for 2 sec.
  • Forty-eight hours after this training phase the rat is placed in the illuminated compartment and the input latency in the dark compartment is measured automatically.
  • F17334 was administered ip immediately after initial training.
  • the device is the same as before, but the electric shock is of higher intensity and the rat receives an injection of scopolamine, a cholinergic antagonist which causes amnesia (Chopin P, Briley M. Effects of four non-cholinergic cognitive enhancers in comparison ith tacrine and galanthamine on scopo 1 amin ei nduced amnesia in rats, Psychopharmacology (Berl), 1992; 106: 26-30). F17334 reverses the cognitive deficit induced by scopolamine in the passive avoidance test ( Figure 4).
  • Figure 4 shows that F17334 administered at the indicated doses increases the latency to enter a compartment associated with electric shock. * P ⁇ 0.05; ** P ⁇ 00.1 versus control animals.
  • F17334 increases cognitive performance in the Morris pool test, using both spatial memory and executive functions (Figure 5).
  • Figure 5 shows that the F17334 increases the time spent in the quadrant where the masked platform is located.
  • the score of 25% of the time spent in this quadrant represents the theoretical time that the animal would spend if it circulated randomly in the pool.
  • the platform Located 1 cm below the water level, the platform is not visible by the animal.
  • Three pooled trials are performed daily. Each test consists of placing the rat in the water, facing the wall. The rat swims freely until he finds the platform on which he climbs quickly. At each test the starting position is different and the time taken to reach the platform is measured. If the animal does not find it in a period of 100 secs, it is then guided by the experimenter. The time interval between 2 tests is 20 secs, during which time the rat remains on the platform. After a predetermined number of training days, the "test" (a single 60-sec test) is performed: the platform is removed and the% of time the animal passes through quadrant Q4 where the platform is determined was initially located.
  • the performance of the animals to find the location of the platform is dependent on the number of days of training. After 3 or 4 days of training, the rats spend in the Q4 quadrant a proportion of time well above the theoretical 25% (25% for each of the 4 quadrants), demonstrating that they have learned the location of the platform in this quadrant. quadrant. After only 1 or 2 days of training, the animals spend the same proportion of time (25%) in each quadrant, demonstrating that they have not learned the location of the platform. Under these conditions, a promnesic effect of the compounds (an increase in the spatial memory performance) can be detected.
  • the F17334 was evaluated by ip administration once at the end of each daily session, and the test is performed 24 hours later.
  • Figure 6 shows the inhibition of ultrasonic vocalizations (SUV) by F17334, administered i.p. at the indicated doses in mg / kg. * P ⁇ 0.05, ** P ⁇ 0.01 versus control animals.

Abstract

The present invention relates to the selection of patients and treating the latter with carpipramine according to criteria relating to the property of carpipramine of preferentially blocking the alpha2C subtype, which can be used to characterize patients capable of benefiting from treatment with carpipramine, and to exclude those having disorders which cannot be improved by carpipramine.

Description

UTILISATION DE LA CARPIPRAMINE DANS LE TRAITEMENT DE TROUBLES PSYCHIATRIQUES ET DU DEVELOPPEMENT CHEZ L'ENFANT ET L'ADOLESCENT L a c a r p i p r a m i n e ( 1 ' - (3- (10, ll-dihydro-5H- dibenzo [b, f ] azepin-5-yl) propyl) -1,4 '-bip iperidine-4' - carboxamide) , commercialisée au Japon depuis 1967 sous le nom de Defekton©, et en France depuis 1976 et en Pologne depuis 1982 sous le nom de Prazinil©, est un antipsychotique atypique indiqué dans le traitement de diverses af fections psychiatriques, dont la schizophrénie, plus particulièrement dans ses formes dites déficitaires ou hébéphréniques , et le contrôle de l' inhibition au cours des états anxieux chez l'adulte .  USE OF CARPIPRAMINE IN THE TREATMENT OF PSYCHIATRIC DISORDERS AND DEVELOPMENT IN CHILDREN AND ADOLESCENTS Acarpipramine (1 '- (3- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) ) propyl) -1,4'-bipiperidine-4'-carboxamide), marketed in Japan since 1967 under the name Defekton ©, and in France since 1976 and in Poland since 1982 under the name Prazinil ©, is an antipsychotic atypical therapy indicated for the treatment of various psychiatric disorders, including schizophrenia, more particularly in the so - called deficient or hebephrenic forms, and the control of inhibition during anxiety states in adults.
Ses propriétés cliniques distinguent la carpipramine à la fois des a n t i p s y ch o t i qu e s et des antidépresseurs . Les indications de la carpipramine se rassemblent autour d' un dénominateur commun : les déficits fonctionnels de l'activité et de l' humeur, qui sont au premier plan dans l' évolution déficitaire des psychoses, dans l' asthénie névrotique, le retrait autistique, ou qui succèdent fréquemment aux cures de sevrage des toxicomanes (Deniker P, Ginestet D, Lôo H (1975) Psychotropic drugs and mechanisms of mood régulation . L'Encéphale, l (4) :359-362 ; Lôo H (1978) Inhibition and psychotropic agents. Therapeutic disinhibitory agents. L' Encéphale, 4 (Suppl 5) :527-532) . L'originalité de l a carpipramine réside dans son action désinhibitrice marquée en dehors de toute activité thymoanaleptique vraie. L' absence d'accélération idéique associée à l'absence de dépendance distingue cette action de celle des composés psychostimulants de type amphétaminique .  Its clinical properties distinguish carpipramine from both anti-depressants and anti-depressants. The indications for carpipramine come together around a common denominator: functional deficits of activity and mood, which are at the forefront in the deficit evolution of psychoses, in neurotic asthenia, autistic withdrawal, or who frequently follow drug withdrawal treatment (Deniker P, Ginestet D, Lôo H (1975) Psychotropic Drugs and Mechanisms of Mood Regulation.) The Brain, l (4): 359-362; Lôo H (1978) Inhibition and psychotropic agents, Therapeutic disinhibitory agents, Encephalon, 4 (Suppl 5): 527-532). The originality of carpipramine lies in its marked disinhibiting action outside of any true thymoanaleptic activity. The absence of ideical acceleration associated with the absence of dependence distinguishes this action from that of psychostimulant compounds of amphetamine type.
La carpipramine a été aussi utilisée chez l' enfant et l'adolescent pour traiter des psychoses infantiles, notamment représentées par des éléments autistiques (Tridon P and Mises R (1978) La carpipramine en pédopsychiatrie. L'Encéphale, 4:587- 594; Danjoux J, Moron P (1979) The effect of an inhibition- counteracting agent in the adolescent. Neuropsychiatr . Enfance Adolesc. 27(6) :293-297) . Les données cliniques de ces études anciennes chez l'enfant et l'adolescent montraient une hétérogénéité de la réponse thérapeutique, dans des cas étudiés eux-mêmes hétérogènes dans leur caractérisation nosographique , aujourd'hui caduque au regard des classifications nosographiques actuelles. De plus, les évaluations d'efficacité étaient de type descriptif, et ne répondaient pas aux critères d'efficacité actuels fondés sur des échelles d'évaluation validées. Carpipramine has also been used in children and adolescents to treat pediatric psychoses, including autistic elements (Tridon P and Mises R (1978) Carpipramine in Child Psychiatry, Brain, 4: 587-594; Danjoux J, Moron P (1979) The effect of an inhibition- counteracting agent in the teenager. Neuropsychiatric. Teenage childhood. 27 (6): 293-297). The clinical data of these old studies in children and adolescents showed a heterogeneity of the therapeutic response, in studied cases themselves heterogeneous in their nosographic characterization, nowadays obsolete compared to current nosographic classifications. In addition, the effectiveness evaluations were descriptive in nature, and did not meet the current effectiveness criteria based on validated rating scales.
Les troubles psychopathologiques chez l'enfant et l'adolescent sont aujourd'hui définis comme appartenant aux catégories diagnostiques suivantes, selon une approche multiaxiale intégrant les troubles répertoriés à la fois dans le CIM-10 (10ème édition du «International Statistical Classification of Diseases and Related Health Problems», ICD-10, Classification of Mental and Behavioral Disorders : diagnostic criteria for research, World Health Organization, 1993 revised 1997, dans le DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatrie Association, 2004) et la CFTMEA-R, Classification Française des Troubles Mentaux de l'Enfant et de l'Adolescent (Mises, Quemada, CFTMEA R 2000, CTNERHI, Paris 2002 ; C. Bursztejn, P. Jeammet . Autisme et psychoses de l'enfant dans la CFTMEA R-2000- Autism and children psychoses in the CFTMEA R- 2000, Annales médico- psychologiques, Vol 160, numéro 3, 216-219 , 2002) . Des correspondances ont été établies entre ces classifications. Elles recouvrent d'une manière générale les cadres nosographiques suivants : Psychopathological disorders in children and adolescents are now defined as belonging to the following diagnostic categories, according to a multiaxial approach integrating the disorders listed in both the ICD-10 (10 th edition of the "International Statistical Classification of Diseases"). and Related Health Problems, "ICD-10, Classification of Mental and Behavioral Disorders: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, 1993 revised 1997, in the DSM-IV. , 2004) and the CFTMEA-R, French Classification of Mental Disorders in Children and Adolescents (Mises, Quemada, CFTMEA 2000, CTNERHI, Paris 2002, C. Bursztejn, P. Jeammet, Autism and psychoses of the in the CFTMEA R-2000- Autism and Children Psychoses in the CFTMEA R-2000, Medico-psychological Annals, Vol 160, Number 3, 216-219, 2002). established between these classifications. They generally cover the following nosographic frameworks:
les troubles envahissants du développement, - les troubles désintégratifs de l'enfant et de pervasive developmental disorders, - disintegrative disorders of the child and of
1 ' adolescent , 1 teenager,
les psychoses précoces déficitaires,  the early psychoses deficit,
les dysharmonies psychotiques,  psychotic disharmony,
les troubles envahissants du développement non spécifiés,  pervasive developmental disorders not specified,
les autismes, les troubles de l'humeur à forme atypique. autism, atypical mood disorders.
L'origine de l'activité clinique singulière de la carpipramine est mal connue, si bien qu'il est impossible d'associer ses propriétés pharmacologiques avec une efficacité particulière vis-à-vis de symptômes, ou bien dans une catégorie nosographique . La variabilité et 1 ' imp r édi c t ibi 1 i t é de la réponse thérapeutique, telles que rapportées dans les études antérieures, limite aujourd'hui l'usage clinique de la carpipramine .  The origin of the singular clinical activity of carpipramine is poorly understood, so that it is impossible to associate its pharmacological properties with a particular efficacy with respect to symptoms, or in a nosographic category. The variability and urgency of the therapeutic response, as reported in previous studies, now limits the clinical use of carpipramine.
Si la pharmacologie de la carpipramine est si mal connue, notamment en termes d'interactions avec les récepteurs cérébraux, c'est qu'elle a été établie bien avant l'avènement de la biologie moléculaire dans le domaine et la découverte à partir du milieu des années 80 de l'existence de nombreux récepteurs pour les neuromédiateurs noradrénaline , sérotonine et dopamine. Cette pharmacologie a été depuis étudiée de manière très occasionnelle. La carpipramine est connue comme antagoniste des récepteurs 5-HT2 de la sérotonine (Sechter D, and Lôo H (1990) 5 HT2 antagonists and carpipramine. Rev. Prat . 40 (25) : 2363-2365) , et comme antagoniste des récepteurs D2 et D3 de la dopamine (Sokoloff P, Andrieux M, Besançon R, Pilon C, Martres MP, Giros B, Schwartz JC (1992) Pharmacology of human dopamine D3 receptor expressed in a mammalian cell line: comparison ith D2 receptor. Eur. J. Pharmacol . 225(4) : 331-337) . La carpipramine est aussi un antagoniste des récepteurs alphal et alpha2 adrénergiques (Setoguchi M, Sakamori M, Takehara S, Fukuda T (1985) Effects of iminodibenzyl antipsychotic drugs on cérébral dopamine and alpha-adrenergic receptors. Eur. J. Pharmacol. 112 (3) : 313-322) .  If the pharmacology of carpipramine is so poorly understood, particularly in terms of interactions with brain receptors, it is that it was established well before the advent of molecular biology in the field and the discovery from the middle 1980s existence of many receptors for the neuromediators norepinephrine, serotonin and dopamine. This pharmacology has since been studied very occasionally. Carpipramine is known to antagonize serotonin 5-HT2 receptors (Sechter D, and Lôo H (1990) 5 HT2 antagonists and carpipramine, Rev. Prat 40 (25): 2363-2365), and as a D2 receptor antagonist. and D3 of dopamine (Sokoloff P, Andrieux M, Besançon R, Pilon C, Martres MP, Giros B, Schwartz JC (1992) Pharmacology of human dopamine D3 receptor expressed in a mammalian cell line: comparison ith D2 receptor Eur J Pharmacol 225 (4): 331-337). Carpipramine is also an antagonist of alphal and alpha2 adrenergic receptors (Setoguchi M, Sakamori M, Takehara S, Fukuda T (1985) Effects of iminodibenzyl antipsychotic drugs on brain dopamine and alpha-adrenergic receptors, Eur J. Pharmacol 112 (3). ): 313-322).
Les récepteurs alpha2 adrénergiques, qui jouent un rôle critique dans la régulation de l'activité neuronale et de la libération des neurotransmetteurs (Ruffolo RR Jr, Nichols AJ, Stadel JM, Hieble JP (1993) Pharmacologie and therapeutic applications of alpha2-adrenoceptor subtypes. Annu. Rev. Pharmacol. Toxicol . 33:243-79), sont constitués de trois sous- types génétiquement et fonctionnellement distincts : alpha2A, alpha2B et alpha2C. Le sous-type alpha2A est le plus abondant des 3 sous-types et est largement distribué dans tout l'organisme, y compris dans le cerveau où il est présent en particulier sur les neurones noradrénergiques pour contrôler la libération de noradrénaline . Dans le cerveau, la présence du sous-type alpha2B est restreinte au thalamus et très limitée en niveau de l'expression, comparé à celui d'organes périphériques comme le rein. La distribution du récepteur alpha2C dans le système nerveux central est trouvée principalement dans des zones telles que le tubercule olfactif, le striatum et l'hippocampe, le locus coeruleus et d'autres régions du cerveau contenant les corps cellulaires des neurones noradrénergiques, et dans les centres dopaminergiques du mésencéphale , comme la substance noire et la zone tegmentale ventrale. Alpha2 adrenergic receptors, which play a critical role in the regulation of neuronal activity and release of neurotransmitters (Ruffolo RR Jr, AJ Nichols, Stadel JM, Hieble JP (1993) Pharmacology and therapeutic applications of alpha2-adrenoceptor subtypes. Annu Rev. Pharmacol Toxicol 33: 243-79), consist of three genetically and functionally distinct subtypes: alpha2A, alpha2B and alpha2C. The alpha2A subtype is the most abundant of the 3 subtypes and is widely distributed throughout the body, including the brain where it is present in particular on noradrenergic neurons to control the release of norepinephrine. In the brain, the presence of the alpha2B subtype is restricted to the thalamus and very limited in level of expression, compared to that of peripheral organs such as the kidney. The distribution of the alpha2C receptor in the central nervous system is mainly found in areas such as the olfactory tubercle, the striatum and the hippocampus, the locus coeruleus and other brain regions containing the cellular bodies of noradrenergic neurons, and in the dopaminergic centers of the midbrain, such as the black substance and the ventral tegmental zone.
Les récepteurs alpha2 adrénergiques modulent les fonctions du système nerveux central, telles que le tonus sympathique, la vigilance, l'attention et la réactivité vis à vis d'un environnement de stress. En absence de sondes pharmacologiques spécifiques des sous-types de récepteurs alpha2 adrénergiques, une vision de leurs rôles est venue du développement et de l'utilisation de souris génétiquement modifiées, soit par inactivation, par mutation ciblée ou par surexpression de leurs gènes .  Alpha2 adrenergic receptors modulate central nervous system functions, such as sympathetic tone, alertness, attention, and responsiveness to a stress environment. In the absence of specific pharmacological probes for alpha2 adrenergic receptor subtypes, a vision of their roles has come from the development and use of genetically modified mice, either by inactivation, targeted mutation or overexpression of their genes.
Des études comparatives avec ces souris transgéniques ont montré que le sous-type alpha2A est le médiateur principal de la plupart des effets induits par des agonistes alpha2 adrénergiques non sélectifs des sous-types, tels que la sédation, l'analgésie, l'hypothermie, l'inhibition sympathique et la réduction de la pression artérielle. Des tests neuropsychopharmacologiques chez les souris KO (« knock out ») ou sur-exprimant le sous-type alpha2C montrent que le sous-type alpha2C adrénergique a un rôle distinct inhibiteur dans le développement des informations sensorielles, et dans le contrôle des activités cognitives, motrices, émotionnelles ou reliées au stress du système nerveux central (Scheinin M, Sallinen J, Haapalinna A (2001) Evaluation of the alpha2C-adrenoceptor as a neuropsychiatrie drug target studies in transgenic mouse models. Life Sci. 68 (19-20) : 2277-2285) . Comparative studies with these transgenic mice have shown that the alpha2A subtype is the main mediator of most of the effects induced by non-selective subtype alpha2 adrenergic agonists, such as sedation, analgesia, hypothermia, sympathetic inhibition and reduction of arterial pressure. Neuropsychopharmacological tests in KO mice ("knock out") or overexpressing the alpha2C subtype show that the alpha2C adrenergic subtype has a distinct inhibitory role in the development of sensory information, and in the control of cognitive activities, motor, emotional, or stress-related central nervous system (Scheinin M, Sallinen J, Haapalinna A (2001) Evaluation of the alpha2C-adrenoceptor as a neuropsychiatry drug target studies in transgenic mouse models. Life Sci. 68 (19-20): 2277-2285).
Le sous-type alpha2C est exprimé dans les zones qui sont impliquées dans la mémoire et autres fonctions cognitives, engagées par des boucles de rétroaction fronto-striato- thalamiques . Les souris trangéniques sur-exprimant le sous-type alpha2C sont moins performantes dans les tests de mémoire spatiale ou non spatiale de la «piscine de Morris» (Morris R (1984) Developments of a ater-maze procédure for studying spatial learning in the rat. J. Neurosci. Methods 11 ( 1 ) : 47-60 ) , le traitement par un antagoniste alpha2 non sélectif d'un sous- type rétablit un phénotype normal chez ces souris. Il a donc été proposé que les antagonistes sélectifs du sous-type alpha2C pourraient moduler le fonctionnement de la boucle de rétroaction fronto-striato-thalamique de manière plus efficace que les antagonistes alpha2 non sélectif du sous-type alpha2C.  The alpha2C subtype is expressed in the areas that are involved in memory and other cognitive functions, engaged by fronto-striato- thalamic feedback loops. Over-expressing alpha2C transgenic mice perform poorly in the spatial or non-spatial memory tests of the "Morris pool" (Morris R (1984) Developments of ater-maze procedure for studying spatial learning in the rat J. Neurosci, Methods 11 (1): 47-60), treatment with a nonselective alpha2 antagonist of a subtype restores a normal phenotype in these mice. It has therefore been proposed that selective antagonists of the alpha2C subtype could modulate the operation of the fronto-striato-thalamic feedback loop more efficiently than alpha2C non-selective alpha2 antagonists.
Il est bien établi que les antagonistes alpha2 non- préférentiels d'un sous-type, comme le dexefaroxan, facilitent la libération in vivo de neurotransmetteurs qui sont impliqués dans l'apprentissage et la mémoire, y compris 1 ' acétyleholine , la noradrénaline et la dopamine corticale (Marien M, Colpaert FC, Rosenquist AC (2004) Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res. Brain Res . Rev. 45(1) :38-78) . Une contribution spécifique du sous-type alpha2C dans ces effets restait à démontrer expérimentalement, notamment avec une sonde pharmacologique spécifique.  It is well established that non-preferential alpha2 antagonists of a subtype, such as dexefaroxan, facilitate the in vivo release of neurotransmitters that are involved in learning and memory, including acetylcholine, norepinephrine, and cortical dopamine (Marien M, Colpaert FC, Rosenquist AC (2004) Noradrenergic mechanisms in neurodegenerative diseases: Brain Res., Brain Res Rev. 45 (1): 38-78). A specific contribution of the alpha2C subtype in these effects remained to be demonstrated experimentally, in particular with a specific pharmacological probe.
Les inventeurs ont réévalué la pharmacologie de la carpipramine vis-à-vis de différents sous-types de récepteurs pour les neuromédiateurs noradrénaline, dopamine et sérotonine. De manière inattendue, ils ont trouvé que les récepteurs pour lesquels la carpipramine avait le plus d'affinité étaient les sous-types de récepteurs noradrénergiques alpha2B et alpha2C (Exemple 1) . Compte-tenu du rôle présumé du sous-type alpha2C décrit ci-dessus, ils en déduisent que la carpipramine tire son activité clinique de son activité particulière pour le sous-type alpha2C . Pour confirmer le rôle du blocage du sous-type alpha2C dans le spectre d'activité de la carpipramine, le composé F17334, un antagoniste adrénergique préférentiel du sous-type alpha2C (Exemple 2), a été évalué dans divers tests pharmacologiques . Le blocage du sous-type alpha2C par le F17334 a les conséquences suivantes chez le rat ou la souris : The inventors have re-evaluated the pharmacology of carpipramine with respect to different receptor subtypes for the neuromediators noradrenaline, dopamine and serotonin. Unexpectedly, they found that the receptors for which carpipramine had the most affinity were the subtypes of alpha2B and alpha2C noradrenergic receptors (Example 1). Given the presumed role of the alpha2C subtype described above, they conclude that carpipramine derives its clinical activity from its particular activity for the alpha2C subtype. To confirm the role of alpha2C subtype blocking in the carpipramine activity spectrum, compound F17334, a preferred alpha2C subtype adrenergic antagonist (Example 2), was evaluated in various pharmacological tests. Blocking of the alpha2C subtype by F17334 has the following consequences in rats or mice:
une augmentation du métabolisme de la noradrénaline dans le cortex préfrontal et les régions limbiques du cerveau de la souris, et dans une moindre mesure, du métabolisme de la dopamine, alors que celui de la sérotonine reste inchangé ou légèrement augmenté à la plus forte dose. De manière remarquable, la carpipramine présente un profil pharmacologique très similaire à celui du F17334 vis-à-vis des changements des métabolites de la noradrénaline, de la dopamine et de la sérotonine, surtout dans les régions limbiques (Exemple 3) ;  an increase in norepinephrine metabolism in the prefrontal cortex and limbic regions of the mouse brain, and to a lesser extent dopamine metabolism, while that of serotonin remains unchanged or slightly increased at the highest dose. Remarkably, carpipramine has a pharmacological profile very similar to that of F17334 with respect to changes in the metabolites of norepinephrine, dopamine and serotonin, especially in the limbic regions (Example 3);
une réversion du déficit cognitif induit par des faibles chocs électriques dans le test d'évitement passif chez le rat (Exemple 4) ;  a reversion of the cognitive deficit induced by weak electric shocks in the passive avoidance test in the rat (Example 4);
une réversion du déficit cognitif induit par la scopolamine chez le rat (Exemple 5) ;  reversion of scopolamine-induced cognitive deficit in rats (Example 5);
une augmentation des performances cognitives dans le test de la «piscine de Morris» chez le rat, qui fait appel à la fois à la mémoire spatiale et aux fonctions exécutives (Exemple 6) ;  an increase in cognitive performance in the "Morris pool" test in the rat, which uses both spatial memory and executive functions (Example 6);
- enfin une inhibition des vocalisations ultrasonores conditionnées, un effet prédictif d'une activité anti-stress chez le rat (Exemple 7) .  finally, an inhibition of conditioned ultrasonic vocalizations, a predictive effect of an anti-stress activity in rats (Example 7).
Les inventeurs en déduisent que la carpipramine, du fait de ces propriétés de blocage préférentiel du sous-type alpha2C, possède une activité procognitive et anti-stress pouvant améliorer l'apprentissage.  The inventors deduce that carpipramine, because of these preferential blocking properties of the alpha2C subtype, has a procognitive and anti-stress activity that can improve learning.
La présente invention concerne donc une sélection de patients et leur traitement par la carpipramine, suivant des critères en rapport avec la propriété de la carpipramine de bloquer préférentiellement le sous-type alpha2C, qui peut servir, d'une part à caractériser les patients qui peuvent bénéficier du traitement par la carpipramine, et d'autre part à exclure ceux qui présentent des troubles ne pouvant pas être améliorés par la carpipramine. The present invention therefore relates to a selection of patients and their treatment with carpipramine, according to criteria relating to the property of carpipramine preferentially block the alpha2C subtype, which can serve, on the one hand, to characterize patients who can benefit from treatment with carpipramine, and to exclude those with disorders that can not be improved with carpipramine.
Dans le contexte de l'invention, le terme traitement, comme utilisé ici, signifie empêcher ou inhiber la survenue ou la progression, ou inverser la progression de l'affection à laquelle le terme s'applique, ou bien d'un ou de plusieurs symptômes de cette affection.  In the context of the invention, the term treatment, as used herein, means preventing or inhibiting the onset or progression, or reversing the progression of the condition to which the term applies, or one or more symptoms of this condition.
Selon l'invention, le terme patient se réfère à un humain d'un âge compris entre 3 et 30 ans susceptible d'être affecté par un trouble psychiatrique ou neuro-développemental .  According to the invention, the term patient refers to a human of an age between 3 and 30 years likely to be affected by a psychiatric or neuro-developmental disorder.
Dans le contexte de l'invention, les affections appartiennent au spectre des troubles psychiatriques ou des troubles envahissants du développement de l'enfant et de l'adolescent énoncés précédemment, les patients sont sélectionnés selon qu' ils présentent des troubles de l'apprentissage ou de la socialisation.  In the context of the invention, the diseases belong to the spectrum of psychiatric disorders or pervasive developmental disorders of the child and adolescent previously stated, patients are selected according to whether they have learning disorders or of socialization.
Plus spécifiquement selon l'invention, les patients à traiter par la carpipramine ont des troubles des conduites cognitives et de la motivation, en relation avec la communication et le contact avec autrui, mais aussi les différents domaines de l'acquisition et du comportement social.  More specifically according to the invention, patients treated with carpipramine have cognitive behavior and motivation disorders, in relation to communication and contact with others, but also the different areas of acquisition and social behavior.
L'invention concerne la possibilité d'améliorer ou compenser le déficit cognitif dans les diverses fonctions qui sous-tendent les relations sociales, les activités imaginatives , l'expression des émotions, les capacités cognitives, perceptives ou motrices. Le trouble global des modalités de relation du sujet jeune avec autrui et le monde environnant s'accompagne de difficultés caractéristiques du comportement, communes aux pathologies de la sphère psychotique et non psychotique de type développemental et qui peuvent ainsi se spécifier dans une approche dimensionnelle :  The invention relates to the possibility of improving or compensating for cognitive impairment in the various functions that underlie social relations, imaginative activities, the expression of emotions, cognitive, perceptual or motor skills. The global disorder of the modalities of relationship of the young subject with others and the surrounding world is accompanied by behavioral difficulties, common to the pathologies of the psychotic and non-psychotic sphere of the developmental type and which can thus be specified in a dimensional approach:
une perturbation des interactions sociales (rareté des actes intentionnels d'échange avec les autres ;  a disruption of social interactions (scarcity of intentional acts of exchange with others;
- un retrait et un comportement de solitude, passivité dans l'interaction ; une perturbation des communications verbales et non verbales ; - withdrawal and behavior of loneliness, passivity in the interaction; disruption of verbal and non-verbal communications
une attitude catatonique ;  a catatonic attitude;
une inhibition anxieuse avec ou sans tableau psychotique associé et des troubles fonctionnels associés de l'alimentation ou du sommeil ;  anxious inhibition with or without associated psychotic picture and associated functional disorders of diet or sleep;
une manifestation d'angoisse qui majore les problèmes de contact et de communication.  a manifestation of anxiety that increases the problems of contact and communication.
Puisque la cognition et l'apprentissage correspondent à la gestion des processus de traitement de l'information, d'acquisition et de représentation des connaissances mais aussi des croyances, de résolution des problèmes et de planification de l'action, les inventeurs postulent qu'un traitement avec des propriétés désinhibitrices vis-à-vis du stress et agissant sur les capacités d'attention et de motivation, puisse avoir un effet bénéfique seulement chez les patients qui présentent un déficit de la cognition sociale, mais aussi un affaiblissement, voire une abolition des fonctions exécutives et la "cohérence centrale" (Weak central cohérence) dans les situations cliniques sus-mentionnées . Par son activité pharmacologique à composante alpha2C, jusqu'ici inconnue, la carpipramine possède des propriétés cliniques et des indications originales susceptibles d'apporter une réponse thérapeutique en favorisant notamment le «réaménagement névrotique» dans l'asthénie, les réductions d'activité, 1 ' hyperémotivité , 1 ' hypovigilance associées aux troubles psychotiques et développementaux de l'enfant et de l' adolescent. Par la sélection des patients opérée spécifiquement sur la base des propriétés cliniques attendues de la composante alpha2C, l'efficacité du traitement par la carpipramine est améliorée par rapport à son utilisation clinique antérieure sans la sélection des patients. Dans les études antérieures, les patients traités par la carpipramine avaient un spectre large et hétérogène de symptômes incluant ceux non liés à un dysfonctionnement susceptible d'être amélioré par le blocage du sous-type alpha2C, ce qui explique la réponse thérapeutique variable observée alors . Selon l'invention, les patients qui sont exclus pour un traitement par la carpipramine sont ceux qui soufrent de troubles délirants, hallucinatoires, d'agressivité et d' automutilation, pour lesquels d'autres traitements existent, par exemple par la rispéridone (Risperdal©) . Sont aussi exclus les patients présentant des troubles classés par le DSM-IV-TR comme caractérisés par une hyperactivité ou bien un déficit cognitif ou sensoriel profond, pouvant être associé à un trouble neurologique de type encéphalopathique néonatal ou évolutif non congénital, ou encore à une épilepsie partielle ou généralisée. Since cognition and learning correspond to the management of the processes of information processing, acquisition and representation of knowledge, beliefs, problem solving and action planning, the inventors postulate that treatment with disinhibitory properties with respect to stress and acting on attention and motivation abilities, may have a beneficial effect only in patients who have a deficit of social cognition, but also a weakening or even a abolition of executive functions and "central coherence" (Weak central coherence) in the aforementioned clinical situations. Thanks to its previously unknown alpha2C pharmacological activity, carpipramine possesses clinical properties and original indications that can provide a therapeutic response, notably by promoting "neurotic remodeling" in asthenia, activity reductions, 1 hyperemotivity, hypovigilance associated with psychotic and developmental disorders in children and adolescents. Through the selection of patients operated specifically on the basis of the expected clinical properties of the alpha2C component, the efficacy of carpipramine treatment is improved over its previous clinical use without the selection of patients. In previous studies, patients treated with carpipramine had a broad and heterogeneous spectrum of symptoms including those unrelated to dysfunction that could be improved by blocking the alpha2C subtype, which explains the variable therapeutic response observed then. According to the invention, patients who are excluded for treatment with carpipramine are those suffering from delusional, hallucinatory, aggressive and self-injurious disorders, for whom other treatments exist, for example by risperidone (Risperdal © ). Patients with disorders classified by the DSM-IV-TR as characterized by hyperactivity or a profound cognitive or sensory deficit, which may be associated with a neonatal or progressive non-congenital encephalopathic neurological disorder, or partial or generalized epilepsy.
Encore selon l'invention, la carpipramine est utilisée dans ces situations cliniques, sous la forme d' un sel pharmaceutiquement acceptable, choisi parmi les sels inorganiques d'addition d'acides non-toxiques pour le patient auquel ils sont administrés. Le terme « Pharmaceutiquement acceptable » se réfère à des entités moléculaires et des compositions qui ne produisent aucun effet adverse, allergique ou autre réaction indésirable quand elles sont administrées à un animal ou un humain. Des exemples de sels d'addition d'acide pharmaceutiquement acceptables incluent le bromohydrate , le chlorhydrate, le sulfate, le bisulfate, le phosphate, le nitrate, l'acétate, l'oxalate, le valérate, l'oléate, le palmitate, le stéarate, le laurate, le borate, le benzoate, le lactate, le phosphate, le tosylate, le citrate, le maléate, le fumarate, le succinate, le tartrate, les sels de naphthylate, et les semblables. (Voir, par exemple S. M. Berge, et al., (1977) « les sels pharmaceutiques, » J. Pharm. Sci . , 66:1-19) .  Again according to the invention, carpipramine is used in these clinical situations, in the form of a pharmaceutically acceptable salt selected from the inorganic acid addition salts non-toxic for the patient to whom they are administered. The term "pharmaceutically acceptable" refers to molecular entities and compositions that produce no adverse, allergic or other adverse reactions when administered to an animal or human. Examples of pharmaceutically acceptable acid addition salts include bromohydrate, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate salts, and the like. (See, for example, S. M. Berge, et al., (1977) "Pharmaceutical Salts," J. Pharm Sci., 66: 1-19).
La carpipramine est administrée soit seule, soit dans des compositions pharmaceutiques pouvant inclure des excipients pharmaceutiquement acceptables. Quand utilisé ici, le terme excipient pharmaceutiquement acceptable inclut tout diluant, adjuvant ou excipient, tels que des agents préservatifs, des agents de remplissage, des agents désintégrant, mouillant, émulsifiant, dispersant, antibactérien ou antifongique, ou bien encore des agents qui permettent de modifier l'absorption et la résorption intestinale et digestive. L'utilisation de ces milieux ou vecteurs est bien connue de l'homme du métier. Carpipramine is administered either alone or in pharmaceutical compositions which may include pharmaceutically acceptable excipients. When used herein, the term pharmaceutically acceptable excipient includes any diluent, adjuvant or excipient, such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or else agents which provide change the absorption and intestinal and digestive resorption. The use of these media or vectors is well known to those skilled in the art.
Les compositions pharmaceutiques contenant la carpipramine selon l'invention peuvent être administrées par voie orale, parentérale, nasale ou rectale. Préférentiellement , la carpipramine sera administrée par la voie orale dans une formulation appropriée. Les formulations qui conviennent pour être administrées oralement à un patient incluent les unités thérapeutiques telles que des capsules, des cachets ou des comprimés, chacune contenant une quantité prédéterminée de carpipramine ; elles incluent également une poudre ou des granules ; ou une solution ou suspension dans un liquide aqueux ou un liquide non aqueux; ou une émulsion liquide huile/eau ou eau/huile. Encore préférentiellement , ces compositions pharmaceutiques seront particulièrement adaptées à l'enfant et l'adolescent et se présenteront sous la forme d'une émulsion ou d'une solution buvable, sous forme de sirop ou de solution à diluer dans un verre d'eau.  The pharmaceutical compositions containing carpipramine according to the invention can be administered orally, parenterally, nasally or rectally. Preferably, carpipramine will be administered orally in an appropriate formulation. Formulations suitable for oral administration to a patient include therapeutic units such as capsules, cachets or tablets, each containing a predetermined amount of carpipramine; they also include a powder or granules; or a solution or suspension in an aqueous liquid or a non-aqueous liquid; or an oil / water or water / oil liquid emulsion. More preferably, these pharmaceutical compositions will be particularly suitable for children and adolescents and will be in the form of an emulsion or an oral solution, in the form of syrup or solution to be diluted in a glass of water.
Les dosages des compositions pharmaceutiques contenant la carpipramine dans les compositions de l'invention sont ajustés afin d'obtenir une quantité de substance active qui est efficace pour obtenir la réponse thérapeutique désirée pour une composition particulière à la méthode d'administration. Le niveau choisi de dosage dépend donc de l'effet thérapeutique désiré, de la voie de l'administration, de la durée désirée du traitement et d'autres facteurs. Il est ajusté en fonction de l'âge et du poids du patient.  Dosages of the pharmaceutical compositions containing carpipramine in the compositions of the invention are adjusted to obtain an amount of active substance that is effective in achieving the desired therapeutic response for a particular composition in the method of administration. The chosen level of dosage therefore depends on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors. It is adjusted according to the age and weight of the patient.
Préférentiellement , la carpipramine est administrée dans des compositions pharmaceutiquement acceptables où la dose quotidienne de carpipramine, exprimée en base, est comprise entre 5 à 200 mg, prise en une seule ou plusieurs fois par jour. Exemple 1 Preferably, the carpipramine is administered in pharmaceutically acceptable compositions wherein the daily dose of carpipramine, expressed as base, is between 5 to 200 mg, taken in one or more times per day. Example 1
La carpipramine a été évaluée dans une série de tests de liaison de ligands radioactifs à des récepteurs et sous-types de récepteurs humains recombinants, exprimés par des membranes de cellules cultivées. Les méthodes employées ont été décrites dans Ne man-Tancredi A, Assié MB, Martel JC, Cosi C, Slot LB, Palmier C, Rauly-Lestienne I, Colpaert F, Vacher B, Cussac D (2007) F15063, a potential antipsychotic ith D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties . I . In vitro receptor affinity and efficacy profile. Br . J. Pharmacol . 151 (2 ) : 237-252. La constante d'inhibition (Ki) pour chacun des récepteurs a été mesurée et est rapportée dans le tableau suivant :  Carpipramine was evaluated in a series of radioactive ligand binding assays to recombinant human receptor and receptor subtypes, expressed by cultured cell membranes. The methods employed have been described in Ne man-Tancredi A, Assie MB, Martel JC, Cosi C, Slot LB, Palm C, Rauly-Lestienne I, Colpaert F, Vacher B, Cussac D (2007) F15063, a potential antipsychotic ith D2 / D3 antagonist, 5-HT1A agonist and D4 partial agonist properties. I. In vitro receptor affinity and efficacy profile. Br. J. Pharmacol. 151 (2): 237-252. The inhibition constant (Ki) for each of the receptors has been measured and is reported in the following table:
Figure imgf000012_0001
Les courbes d'inhibition de la liaison, respectivement aux sous- types de récepteurs alpha2A, alpha2B et alpha2C, en fonction de la concentration de carpipramine, sont montrées dans la figure 1.
Figure imgf000012_0001
The inhibition curves of the binding, respectively to the alpha2A, alpha2B and alpha2C receptor subtypes, as a function of carpipramine concentration, are shown in Figure 1.
Cette figure 1 montre l'inhibition de la liaison de [3H]RX821002 à des membranes de cellules exprimant les sous- types de récepteurs alpha2A, alpha2B et alpha2C par des concentrations croissantes de carpipramine. Le radioligand a été utilisé à des concentrations de 2 nM, 10 nM et 4 nM pour les récepteurs alpha 2A, 2B et 2C, respectivement. Exemple 2 This Figure 1 shows the inhibition of [3H] RX821002 binding to cell membranes expressing the alpha2A, alpha2B and alpha2C receptor subtypes by increasing concentrations of carpipramine. The radioligand was used at concentrations of 2 nM, 10 nM and 4 nM for alpha 2A, 2B and 2C receptors, respectively. Example 2
Le F17334, (3- ( ( (2R, llbS) -9-methoxy-2 , 3, 4, 6, 7, 11b- hexahydro-lH-pyrido [2, 1-a] isoquinolin-2-yl) methyl) imidazolidine- 2,4-dione), a été utilisé comme prototype d'antagoniste sélectif du sous-type alpha2C. Le F17334 est un antagoniste des sous- types de récepteurs alpha2A, alpha2B et alpha2C, avec les affinités suivantes :  F17334, (3- (((2R, 11bS) -9-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a] isoquinolin-2-yl) methyl) imidazolidine-2,4-dione), was used as a prototype of a selective alpha2C subtype antagonist. F17334 is an antagonist of alpha2A, alpha2B and alpha2C receptor subtypes, with the following affinities:
Figure imgf000013_0001
Figure imgf000013_0001
La méthode est décrite dans Ne man-Tancredi et al., (déjà cité) The method is described in Ne man-Tancredi et al. (Already cited)
Exemple 3 Example 3
Le F17334 ou la carpipramine augmente les taux des métabolites de la noradrénaline (normétanéphrine, NMN) et de la dopamine (acide homovanillique, HVA) , mais pas ou très peu celui de la sérotonine (d'acide 5-hydroxyindole acétique, 5-HIAA) dosés ex vivo dans le cortex préfrontal et les régions limbiques (tubercule olfactif + noyau accumbens + septum) de la souris 1 heure après l'administration en doses uniques croissantes (figure 2) .  F17334 or carpipramine increases the metabolite levels of noradrenaline (normetanephrine, NMN) and dopamine (homovanillic acid, HVA), but not or very little that of serotonin (5-hydroxyindole acetic acid, 5-HIAA ) ex vivo dosed in the prefrontal cortex and limbic regions (olfactory tubercle + nucleus accumbens + septum) of the mouse 1 hour after administration in increasing single doses (Figure 2).
La figure 2 montre les variations des taux tissulaires de normétanéphrine (NMN) et d'acide homovanillique, (HVA) et d'acide 5-hydroxyindole acétique, (5-HIAA) dans le cortex préfrontal (PFC) et les régions limbiques (tubercule olfactif + noyau accumbens + septum, Limbic) sous l'influence d'un traitement par le F17334 ou la carpipramine administrés en doses uniques croissantes. Les niveaux dans les groupes traités sont exprimés en pourcentage d'une solution saline (0,9% NaCl) injectée dans un groupe de souris contrôles. * P <0.05 ; **P < 0.01 versus Les souris contrôles. Méthodes : Les niveaux de la normetanephrine (NMN) et la 3- methoxytyramine (3-MT ) dans les extraits des structures cérébrales, obtenues des rongeurs sacrifiés à la microonde de haute puissance, ont été validés comme des marqueurs de la libération, respectivement, de la noradrenaline et la dopamine (Wood, P.L. and Altar, C.A. : Dopamine release in vivo from nigrostriatal , mesolimbic, and mesocortical neurons: utility of 3-methoxytyramine measurements. Pharmacologi cal Rev. 40, 163- 187, 1988 ; Wood, P.L., Kim, H. and Altar, C.A. : In vivo assessment of dopamine and norepinephrine release in rat neocortex: gas chromatography-mas s spectrometry measurement of 3-methoxytyramine and normetanephrine. J. Neurochem. 48: 574- 579, 1987. Wood et Altar, 1986 ; Wood et al, 1987) . Le F17334 ou la carpipramine étaient solubilisés par sonication dans l'eau ultra-pure (Direct-Q5) , et administrés par voie intraperitonéale (i.p.) chez les souris mâles (NMRI) . Les animaux était sacrifiés 60 min plus tard à la microonde (4.8 kW, 2450 MHz, 0.8 - 1.0 sec ; Sacron, SAIREM) . Les structures cérébrales étaient prélevées, homogénéisé dans une solution d'acide perchlorique , centrifugés et les surnageants analysés directement par HPLC couplé avec détection électrochimique selon la méthode de Cosi et Marien (Cosi C, Marien M. 1998. Decreases in mouse brain NAD+ and ATP induced by l-methyl-4-phenyl-l , 2 , 3 , 6-tetrahydropyridine (MPTP) : prévention by the p o 1 y ( AD P-r ibo se ) polymerase inhibitor, benzamide. Brain Res. 809, 58-67) . Les niveaux des métabolites dans les groupes traités (n = 6-7 souris par groupe) étaient calculés en pmoles/mg tissu et exprimés en pourcentage des niveaux mesurées dans un groupe « contrôle » (animaux injectes i.p. avec une solution du salin physiologique (0.9% NaCl) . Figure 2 shows changes in tissue levels of normetanephrine (NMN) and homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the prefrontal cortex (PFC) and limbic regions (tubercle). olfactory + nucleus accumbens + septum, Limbic) under the influence of treatment with F17334 or carpipramine administered in increasing single doses. The levels in the treated groups are expressed as a percentage of a saline solution (0.9% NaCl) injected into a group of control mice. * P <0.05; ** P <0.01 versus control mice. METHODS: Levels of normetanephrine (NMN) and 3-methoxytyramine (3-MT) in extracts of brain structures obtained from rodents sacrificed in high power microwaves were validated as markers of release, respectively. noradrenaline and dopamine (Wood, PL and Altar, CA: Dopamine release in vivo from nigrostriatal, mesolimbic, and mesocortical neurons: utility of 3-methoxytyramine measurements, Pharmacologi cal Rev. 40, 163- 187, 1988; Wood, PL , Kim, H. and Altar, CA: In vivo assessment of dopamine and norepinephrine release in rat neocortex: gas chromatography-mas spectrometry measurement of 3-methoxytyramine and normetanephrine, J. Neurochem 48: 574-579, 1987. Wood and Altar, 1986, Wood et al, 1987). F17334 or carpipramine were solubilized by sonication in ultrapure water (Direct-Q5), and administered intraperitoneally (ip) in male mice (NMRI). The animals were sacrificed 60 min later to the microwave (4.8 kW, 2450 MHz, 0.8 - 1.0 sec, Sacron, SAIREM). The brain structures were removed, homogenized in a solution of perchloric acid, centrifuged and the supernatants analyzed directly by HPLC coupled with electrochemical detection according to the method of Cosi and Marien (Cosi C, Marien M. 1998. Decreases in mouse brain NAD + and ATP induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): prevention by the polymer (AD Pr ibo se) polymerase inhibitor, benzamide Brain Res 809, 58-67). Metabolite levels in the treated groups (n = 6-7 mice per group) were calculated as pmol / mg tissue and expressed as a percentage of levels measured in a "control" group (ip injection animals with physiological saline solution (0.9 % NaCl).
Exemple 4 Example 4
Le test d' évitement passif consiste à faire apprendre à un rat à ne plus entrer dans un compartiment sombre (sa place de préférence naturelle) où il a précédemment reçu un choc électrique (0.8 mA) . La réticence de l'animal (le laps du temps, ou la « latence », pour entrer dans le compartiment sombre) , mesuré 48 h après son entraînement, est considéré comme une indice de son mémoire explicite-déclarative. La latence augmente en fonction de l'intensité du choc d'entraînement. Un choc de 0.8 raA diminue fortement la latence (augment la « mémoire ») , tandis qu'un faible choc (0.1 mA) n'a aucun effet significatif. Ces 2 conditions donnent la possibilité d'évaluer les propriétés positives (promnésiantes ) et négatives (amnésiantes) des composés sur les capacités d'acquisition, de mémorisation et de rappel de l'animal. Lorsque le choc est de faible intensité, la performance est médiocre mais peut être améliorée par des traitements pharmacologiques procognitifs . Le F17334 améliore la performance cognitive de manière dose-dépendante dans ce test (figure 3) . The passive avoidance test consists of teaching a rat not to enter a dark compartment (its natural place of preference) where it has previously received an electric shock (0.8 mA). Reluctance of the animal (the lapse of time, or "latency", to enter the dark compartment), measured 48 hours after his training, is considered as an index of his explicit-declarative memory. Latency increases with the intensity of the training shock. A shock of 0.8 raA strongly decreases the latency (increases the "memory"), while a weak shock (0.1 mA) has no significant effect. These two conditions give the possibility of evaluating the positive (promnesiant) and negative (amnesic) properties of the compounds on the acquisition, memorization and recall capabilities of the animal. When the shock is of low intensity, the performance is mediocre but can be improved by procognitive pharmacological treatments. F17334 improves cognitive performance in a dose-dependent manner in this test (Figure 3).
La figure 3 représente le F17334 , administré aux doses indiquées, qui augmente la latence à pénétrer dans un compartiment associé au choc électrique. * P <0.05 ; ** P < 00.1 versus les animaux contrôles.  Figure 3 shows F17334, administered at the indicated doses, which increases the latency to enter a compartment associated with electric shock. * P <0.05; ** P <00.1 versus control animals.
Méthode : L'appareillage consiste en un compartiment clair (30 X 30 X 30 cm) connecté à une ouverture (7 X 7 cm) a un compartiment sombre (20 X 20 X 12 cm), équipée d'un plancher en grille métallique. Une lampe (60 W) est positionnée à 60 cm à la verticale du centre du compartiment clair (750 lux) . Initialement, le rat est placé dans le compartiment clair et éclairé, qu'il peut explorer pendant 30 sec. L'entrée du compartiment sombre est alors ouverte et quand le rat a posé ses 4 pattes dans ce compartiment, la porte reliant les 2 compartiments est fermée et le rat reçoit un choc électrique de faible intensité (0.1 mA pendant 2 sec) . Quarante-huit heures après cette phase d'entraînement, le rat est placé dans le compartiment éclairé et le temps de latence d'entrée dans le compartiment sombre est mesuré automatiquement. Le F17334 a été administré par voie i.p. immédiatement après l'entraînement initial . Exemple 5 Method: The apparatus consists of a clear compartment (30 X 30 X 30 cm) connected to an opening (7 X 7 cm) to a dark compartment (20 X 20 X 12 cm), equipped with a metal grid floor. A lamp (60 W) is positioned 60 cm above the center of the light compartment (750 lux). Initially, the rat is placed in the bright and light compartment, which it can explore for 30 sec. The entrance of the dark compartment is then open and when the rat has put its 4 legs in this compartment, the door connecting the 2 compartments is closed and the rat receives a low intensity electric shock (0.1 mA for 2 sec). Forty-eight hours after this training phase, the rat is placed in the illuminated compartment and the input latency in the dark compartment is measured automatically. F17334 was administered ip immediately after initial training. Example 5
Le dispositif est le même que précédemment, mais le choc électrique est de plus forte intensité et le rat reçoit une injection de scopolamine, un antagoniste cholinergique qui provoque une amnésie (Chopin P, Briley M. Effects of four non- cholinergic cognitive enhancers in comparison ith tacrine and galanthamine on s c o p o 1 a m i n e-i n d u c e d amnesia in rats, Psychopharmacology (Berl) , 1992;106:26-30) . Le F17334 réverse le déficit cognitif induit par la scopolamine dans le test d' évitement passif (figure 4) .  The device is the same as before, but the electric shock is of higher intensity and the rat receives an injection of scopolamine, a cholinergic antagonist which causes amnesia (Chopin P, Briley M. Effects of four non-cholinergic cognitive enhancers in comparison ith tacrine and galanthamine on scopo 1 amin ei nduced amnesia in rats, Psychopharmacology (Berl), 1992; 106: 26-30). F17334 reverses the cognitive deficit induced by scopolamine in the passive avoidance test (Figure 4).
La figure 4 montre que Le F17334 administré aux doses indiquées, augmente la latence à pénétrer dans un compartiment associé au choc électrique. * P <0.05 ; ** P < 00.1 versus les animaux contrôles.  Figure 4 shows that F17334 administered at the indicated doses increases the latency to enter a compartment associated with electric shock. * P <0.05; ** P <00.1 versus control animals.
Méthode : identique au précèdent, sauf que le choc électrique est de 0.8 raA pendant 2 sec et que le F17334 et la scopolamine (2.5 mg/kg) ont été administrés respectivement 35 et 30 min par voie i.p. avant le test initial. Exemple 6  Method: same as above, except that the electric shock is 0.8 raA for 2 sec and that F17334 and scopolamine (2.5 mg / kg) were administered respectively 35 and 30 min i.p. before the initial test. Example 6
Le F17334 augmente la performance cognitive dans le test de la piscine de Morris, faisant appel à la fois à la mémoire spatiale et aux fonctions exécutives (figure 5) .  F17334 increases cognitive performance in the Morris pool test, using both spatial memory and executive functions (Figure 5).
La figure 5 montre que le F17334 augmente le temps passé dans le quadrant où se trouve la plateforme masquée. Le score de 25% du temps passé dans ce quadrant représente le temps théorique que passerait l'animal s'il circulait au hasard dans la piscine. * P< 0.05 ; ** P <0.01 par rapport au véhicule. + P <0.05 par rapport au score théorique de 25%.  Figure 5 shows that the F17334 increases the time spent in the quadrant where the masked platform is located. The score of 25% of the time spent in this quadrant represents the theoretical time that the animal would spend if it circulated randomly in the pool. * P <0.05; ** P <0.01 compared to the vehicle. + P <0.05 compared to the theoretical score of 25%.
Méthode : la procédure expérimentale chez le rat a été décrite en détail par Chopin et al (Chopin P., Colpaert F.C. and Marien M. Effects of acute and subchronic administration of dexefaroxan, an alpha2-adrenoceptor antagonist, on memory performance in young adult and aged rodents. J. Pharmacol . Exp. Ther. 301: 187-196, 2002) . L'expérience se déroule dans une piscine circulaire de 180 cm de diamètre et de 60 cm de hauteur remplie d'eau (maintenue à 25 ± 1°C) jusqu'à une hauteur de 30 cm. Quatre points cardinaux situés sur le bord de la piscine délimitent 4 quadrants virtuels (Ql, Q2 , Q3, Q4) . Une plateforme d'un diamètre de 10 cm et d'une hauteur de 29 cm occupe une place fixe au centre du quadrant Q4. Située 1 cm au-dessous du niveau de l'eau, la plate-forme n'est pas visible par l'animal. Trois essais groupés sont réalisés par jour. Chaque essai consiste à placer le rat dans l'eau, face à la paroi. Le rat nage alors librement jusqu'à ce qu'il trouve la plate-forme sur laquelle il grimpe rapidement. A chaque essai la position de départ est différente et l'on mesure le temps mis pour atteindre la plate-forme. Si l'animal ne la trouve pas dans un laps de temps de 100 secs, il est alors guidé par l'expérimentateur. L'intervalle de temps entre 2 essais est de 20 secs, temps durant lequel le rat reste sur la plate-forme. Après un nombre prédéterminé de jours d' entraînement, le « test » (un seul essai de 60 secs) est réalisé : la plateforme est retirée et on détermine le % de temps que l'animal passe dans le quadrant Q4 où la plate-forme était initialement située. Les performances des animaux pour trouver l'endroit de la plate-forme sont dépendantes du nombre des jours d' entraînement . Après 3 ou 4 jours d' entraînement , les rats passent dans le quadrant Q4 une proportion de temps bien supérieur au 25% théorique (25% pour chacun des 4 quadrants) , démontrant qu'ils ont appris l'emplacement de la plateforme dans ce quadrant. Après seulement 1 ou 2 jours d' entraînement , les animaux passent la même proportion de temps (25 %) dans chaque quadrant, démontrant qu'ils n'ont pas appris la localisation de la plateforme. Dans ces conditions, un effet promnésique des composés (une augmentation de la performance de mémoire spatiale) peut être détecté. Le F17334 a été évalué par administration i.p. une fois à la fin de chaque session journalière, et le test est effectué 24 h plus tard. Exemple 7 Method: The experimental procedure in the rat was described in detail by Chopin et al (Chopin P., Colpaert FC and Marien M. Effects of acute and subchronic administration of dexefaroxan, an alpha2-adrenoceptor antagonist, aged rodents J. Pharmacol Exp Ther 301: 187-196, 2002). The experience takes place in a circular pool 180 cm in diameter and 60 cm in height filled with water (maintained at 25 ± 1 ° C) to a height of 30 cm. Four cardinal points located on the edge of the pool delimit 4 virtual quadrants (Ql, Q2, Q3, Q4). A platform with a diameter of 10 cm and a height of 29 cm occupies a fixed place in the center of quadrant Q4. Located 1 cm below the water level, the platform is not visible by the animal. Three pooled trials are performed daily. Each test consists of placing the rat in the water, facing the wall. The rat swims freely until he finds the platform on which he climbs quickly. At each test the starting position is different and the time taken to reach the platform is measured. If the animal does not find it in a period of 100 secs, it is then guided by the experimenter. The time interval between 2 tests is 20 secs, during which time the rat remains on the platform. After a predetermined number of training days, the "test" (a single 60-sec test) is performed: the platform is removed and the% of time the animal passes through quadrant Q4 where the platform is determined was initially located. The performance of the animals to find the location of the platform is dependent on the number of days of training. After 3 or 4 days of training, the rats spend in the Q4 quadrant a proportion of time well above the theoretical 25% (25% for each of the 4 quadrants), demonstrating that they have learned the location of the platform in this quadrant. quadrant. After only 1 or 2 days of training, the animals spend the same proportion of time (25%) in each quadrant, demonstrating that they have not learned the location of the platform. Under these conditions, a promnesic effect of the compounds (an increase in the spatial memory performance) can be detected. The F17334 was evaluated by ip administration once at the end of each daily session, and the test is performed 24 hours later. Example 7
Des stimuli stressants ou douloureux produisent une série de réponses physiologiques et comportementales chez l'animal, qui souvent se manifestent par l'émission de cris de détresse ultrasonores caractéristiques, à 22 KHz. Par exemple, les rats émettent ces ultrasons lorsqu'ils sont confrontés à un choc électrique inévitable. Dans le test, le choc électrique qui est délivré est associé de manière répétée avec un signal lumineux, si bien que l'exposition ultérieure au signal lumineux seul induit l'émission d'ultrasons. Le F17334 diminue très significativement les vocalisations ultrasonores (figure 6), ce qui indique la capacité du produit à exercer une action antistress .  Stressful or painful stimuli produce a series of physiological and behavioral responses in the animal, which are often manifested by the emission of characteristic ultrasonic distress calls at 22 KHz. For example, rats emit these ultrasounds when confronted with an unavoidable electric shock. In the test, the electric shock that is delivered is repeatedly associated with a light signal, so that the subsequent exposure to the light signal alone induces the emission of ultrasound. F17334 significantly decreases ultrasound vocalizations (Figure 6), indicating the ability of the product to exert an antistress action.
La figure 6 montre l'inhibition des vocalisations ultrasonores (VUS) par le F17334, administré par voie i.p. aux doses indiquées en mg/kg. * P< 0.05, ** P< 0.01 versus les animaux contrôles.  Figure 6 shows the inhibition of ultrasonic vocalizations (SUV) by F17334, administered i.p. at the indicated doses in mg / kg. * P <0.05, ** P <0.01 versus control animals.
Méthode : La procédure a été réalisée comme décrit en détail par (BARDIN, L., GREGOIRE, S., ALIAGA, M., MALFETES, . , VITTON, 0., LADURE, P., NEWMAN-TANCREDI , A. & DEPOORTERE, R. (2010) . Comparison of milnacipran, duloxetine and pregabalin in the formalin pain test and in a model of s t r e s s-induced ultrasonic vocalizations in rats. Neurosci. Res . 66, 135-140.) . Succinctement, les rats ont été entraînés à associer des chocs électriques inévitables (sinusoïdale, 0,4 mA, durée de 1 s) à un stimulus lumineux conditionné. Pendant les sessions de test, les rats ont été injectés i.p. (10 ml / kg) avec le F13987 ou un véhicule, 30 min avant d'être placé dans la cage pour l'enregistrement automatique du nombre de vocalisations ultrasonores (environ 22 kHz) en utilisant le système Ultravox (Noldus, Wageningen, Pays-Bas) . Au cours de ces séances d'essais, seul le premier choc a été délivré avec le stimulus conditionnel; par la suite, seul le stimulus conditionnel a été présenté .  Method: The procedure was carried out as described in detail by (BARDIN, L., GREGOIRE, S., ALIAGA, M., MALFETES,., VITTON, 0., LADURE, P., NEWMAN-TANCREDI, A. & DEPOORTERE , R. (2010).) Comparative of Milnacipran, Duloxetine and Pregabalin in the Formalin Pain and In a Model of Serious Ultrasonic Vocalizations in Neurosci Res, 66, 135-140. Briefly, the rats were trained to combine unavoidable electrical shocks (sinusoidal, 0.4 mA, duration of 1 s) with a conditioned light stimulus. During the test sessions, the rats were injected i.p. (10 ml / kg) with F13987 or a vehicle, 30 min before being placed in the cage for automatic recording of the number of ultrasonic vocalizations (about 22 kHz) using the Ultravox system (Noldus, Wageningen, Netherlands). Low). During these test sessions, only the first shock was delivered with the conditional stimulus; subsequently, only the conditional stimulus was presented.

Claims

Revendications claims
1. La carpipramine pour son utilisation comme médicament dans le traitement des troubles psychiatriques ou des troubles envahissants du développement, chez des patients présentant des troubles de conduite cognitive et de la motivation en relation avec la communication, le contact avec autrui et les différents domaines de l'acquisition et du comportement social ; à l'exclusion des patients présentant des troubles hallucinatoires et délirants, d'agressivité et d'auto-mutilation, d' hyperactivité, ou bien un déficit cognitif profond ou sensoriel profond, les patients présentant un trouble neurologique de type encéphalopathique néonatal ou évolutif non congénital ou encore une épilepsie partielle ou généralisée. 1. Carpipramine for use as a medicine in the treatment of psychiatric disorders or pervasive developmental disorders, in patients with cognitive behavior disorders and motivation in relation to communication, contact with others and the different areas of acquisition and social behavior; excluding patients with hallucinatory and delusional disorders, aggression and self-mutilation, hyperactivity, or profound cognitive or profound cognitive impairment, patients with neonatal or non-progressive encephalopathic neurological disorder congenital or partial or generalized epilepsy.
2. La carpipramine pour son utilisation selon la revendication 1 chez des patients ayant reçu le diagnostic de troubles envahissant du développement, qu'il soit spécifié ou non spécifié.  2. Carpipramine for use according to claim 1 in patients diagnosed with developmental invasiveness, whether specified or unspecified.
3. La carpipramine pour son utilisation selon la revendication 1 chez des patients ayant reçu le diagnostic de troubles désintégratifs de l'enfant et de l'adolescent.  3. Carpipramine for use as claimed in claim 1 in patients diagnosed with disintegrative disorders in children and adolescents.
4. La carpipramine pour son utilisation selon la revendication 1 chez des patients ayant reçu le diagnostic de psychose précoce déficitaire.  4. Carpipramine for use according to claim 1 in patients diagnosed with early deficit psychosis.
5. La carpipramine pour son utilisation selon la revendication 1 chez des patients ayant reçu le diagnostic de dysharmonies psychotiques.  5. Carpipramine for use according to claim 1 in patients diagnosed with psychotic disharmony.
6. La carpipramine pour son utilisation selon la revendication 1 chez des patients ayant reçu le diagnostic d'autisme.  6. Carpipramine for use as claimed in claim 1 in patients diagnosed with autism.
7. La carpipramine pour son utilisation selon la revendication 1 chez des patients ayant reçu le diagnostic de troubles de l'humeur à forme atypique.  7. Carpipramine for use as claimed in claim 1 in patients diagnosed with atypical mood disorders.
8. La carpipramine pour son utilisation selon l'une des revendications 1 à 7 chez des patients âgés de 3 à 18 ans. 8. Carpipramine for use according to one of claims 1 to 7 in patients aged 3 to 18 years.
9. Compositions pharmaceutiques comprenant au moins un excipient pharmaceutiquement acceptable et de la carpipramine à titre de principe actif, pour son utilisation en tant que médicament dans le traitement des troubles psychiatriques ou des troubles envahissants du développement, chez des patients présentant des troubles de conduite cognitive et de la motivation en relation avec la communication, le contact avec autrui et les différents domaines de l'acquisition et du comportement social ; à l'exclusion des patients présentant des troubles hallucinatoires et délirants, d'agressivité et d'auto- mutilation, d' hyperactivité , ou bien un déficit cognitif profond ou sensoriel profond, les patients présentant un trouble neurologique de type encéphalopathique néonatal ou évolutif non congénital ou encore une épilepsie partielle ou généralisée. 9. Pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and carpipramine as an active ingredient for use as a medicament in the treatment of psychiatric disorders or pervasive developmental disorders in patients with cognitive behavior disorders and motivation in relation to communication, contact with others and the different domains of acquisition and social behavior; excluding patients with hallucinatory and delusional disorders, aggression and self-mutilation, hyperactivity, or profound cognitive or profound cognitive impairment, patients with neonatal or non-progressive encephalopathic congenital or partial or generalized epilepsy.
10. Compositions pharmaceutiques selon la revendication 9 chez des patients ayant reçu le diagnostic de troubles envahissant du développement, qu'il soit spécifié ou non spécifié .  10. Pharmaceutical compositions according to claim 9 in patients diagnosed with developmental invasiveness, whether specified or unspecified.
11. Compositions pharmaceutiques selon la revendication 9 chez des patients ayant reçu le diagnostic de troubles désintégratifs de l'enfant et de l'adolescent.  Pharmaceutical compositions according to claim 9 in patients diagnosed with disintegrative disorders in children and adolescents.
12. Compositions pharmaceutiques selon la revendication 9 chez des patients ayant reçu le diagnostic de psychose précoce déficitaire .  Pharmaceutical compositions according to claim 9 in patients diagnosed with early deficit psychosis.
13. Compositions pharmaceutiques selon la revendication 9 chez des patients ayant reçu le diagnostic de dysharmonies psychotiques .  13. Pharmaceutical compositions according to claim 9 in patients diagnosed with psychotic disharmony.
14. Compositions pharmaceutiques selon la revendication 9 chez des patients ayant reçu le diagnostic d'autisme.  14. Pharmaceutical compositions according to claim 9 in patients diagnosed with autism.
15. Compositions pharmaceutiques selon la revendication 9 chez des patients ayant reçu le diagnostic de troubles de l'humeur à forme atypique.  15. Pharmaceutical compositions according to claim 9 in patients diagnosed with atypical mood disorders.
16. Compositions pharmaceutiques selon les revendications 9 à 15, caractérisées à ce que le dosage quotidien de la carpipramine est compris entre 5 et 200 mg. 16. Pharmaceutical compositions according to claims 9 to 15, characterized in that the daily dosage of carpipramine is between 5 and 200 mg.
17. Compositions pharmaceutiques selon les revendications 9 à 16, caractérisées en ce qu'elles sont administrées en une prise quotidienne. 17. Pharmaceutical compositions according to claims 9 to 16, characterized in that they are administered in a daily dose.
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WO2015086836A1 (en) * 2013-12-13 2015-06-18 Pierre Fabre Medicament A chromone derivative as a dopamine d3 receptor antagonist for its use for the treatment of autism spectrum disorder
CN105792824A (en) * 2013-12-13 2016-07-20 皮埃尔法布雷医药公司 A chromone derivative as a dopamine d3 receptor antagonist for its use for the treatment of autism spectrum disorder
US10028948B2 (en) 2013-12-13 2018-07-24 Pierre Fabre Medicament Chromone derivative as a dopamine D3 receptor antagonist for its use for the treatment of autism spectrum disorder
CN105792824B (en) * 2013-12-13 2018-08-03 皮埃尔法布雷医药公司 Chromone derivative is used to treat the purposes of autism spectrum disorder as dopamine D 3 receptor antagonist
RU2686110C1 (en) * 2013-12-13 2019-04-24 Пьер Фабр Медикамент Chromine derivative as dopamine d3 receptor antagonist for application in treating autism spectrum disorder
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