Carbamoyl cyclohexane derivatives for treating autism spectrum disorder

Abstract

To provide a compound for use in the treatment of general symptoms of autism spectrum disorder.SOLUTION: Provided are trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea (cariprazine), its salts, close analogs, derivatives, pharmaceutical compositions, metabolites, and combinations for treating one or more symptoms of autism. These are also suitable for the treatment of conditions such as Asperger's syndrome, atypical autism (otherwise known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD), and sensory integration dysfunction.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea (cariprazine), its salts, close analogs, derivatives, pharmaceutical compositions, metabolites and combinations, for use in the treatment of symptoms of autism spectrum disorder. [Background technology]

[0002] Autism spectrum disorder (ASD) is a complex, challenging, and prevalent neurodevelopmental condition with a prevalence ranging from 1:34 to 1:77 (mean 1:59) in the pediatric population across 11 states in the United States in 2014 (CDC Morbidity and Mortality Weekly Report Surveillance Summaries, April 27, 2018, 67(6):1-23). ​​Based on numerous epidemiological studies, the median prevalence estimate for ASD was 62 / 10,000 in 2012 (Elsabbagh et al., Autism Res. 2012, 5:160-179). As such, ASD is now recognized as a global, common, lifelong neurodevelopmental disorder affecting approximately 1% of both children and adults (Brugha et al., Arch. Gen. Psychiatry. 2011, 68:459-465; Murphy et al., Neuropsychiatr. Dis. Treat. 2016, 12:1669-1686).

[0003] This disorder is characterized by two core symptoms: social-communicative dysfunction and restricted (repetitive, stereotyped) behaviors and thoughts (Diagnostic and Statistical Manual of Mental Disorders, 15th ed., pp. 50-59). Social impairments include abnormal social approaches, failure to normally reciprocate, and failure to initiate and engage in communication. Communication deficits may include poorly integrated verbal and nonverbal communication, abnormal eye contact and body language, impaired understanding of gestures, and a lack of facial expression. In general, deficits in developing, maintaining, and understanding relationships, adapting to social situations, and sharing creative play may be present, as well as a lack of interest in peers. Other core symptom areas may include stereotyped or repetitive mechanical movements, preoccupation with monotony and routine, intense interests that are abnormal in intensity or focus, and abnormal sensory reactivity.

[0004] In addition to the core symptoms, ASD is often accompanied by associated or comorbid symptoms including intellectual disability, attention deficits, hyperactivity, mood disorders, seizures, sleep disorders, etc. A further common area of ​​associated symptoms is irritability, including angry outbursts, aggression towards others, self-injurious behaviors, and mood swings.

[0005] The unmet medical need in ASD is enormous because there are currently no pharmacological treatments available for the treatment of core symptoms in ASD. While there are no approved medications for the treatment of core symptoms, only two antipsychotics from the same class—risperidone and aripiprazole—are approved by the U.S. Food and Drug Administration for the treatment of ASD-related irritability in children aged 5 to 16 years. Aripiprazole is also approved for this purpose in Japan. Although much effort has been poured into clinical research, no effective pharmacological treatments have been identified to date for alleviating the core symptom domains of ASD.

[0006] Risperidone and aripiprazole are atypical antipsychotics with distinct receptor profiles in vitro. Risperidone binds to serotonin 5-HT 2A It is known that it binds with high affinity to the dopamine receptor and acts as an antagonist of the receptor, whereas aripiprazole binds to dopamine D2, D3, and 5-HT 1A and 5-HT 2B It exhibits high affinity for dopamine D2, D3, and serotonin 5-HT receptors. 1A It behaves as a partial agonist at the receptor (Shahid et al., J. Psychopharmacol. 2009, 23:65-73; Tadori et al., Eur. J. Pharmacol. 2011, 668:355-365; Shapiro et al., Neuropsychopharmacol. 2003, 28:1400-1411). It is important to note that both aripiprazole and risperidone occupy dopamine D2 receptors in the human brain (Muly et al., J. Pharmacol. Exp. Ther. 2012, 341:81-89; Grunder et al., Am. J. Psychiatry 2008, 165:988-995). However, neither of these two compounds has been demonstrated to occupy dopamine D3 receptors in humans (Graff-Guerrero et al., Arch. Gen Psychiatry 2009, 66:606-615).

[0007] Although risperidone and aripiprazole have been used to treat irritability associated with ASD, these antipsychotic compounds are not approved or used to treat the core symptom domain of ASD. Clinical studies of the utility of risperidone and aripiprazole in treating core symptoms have shown conflicting results, demonstrating a lack of efficacy for aripiprazole and mixed results for risperidone. Aripiprazole has been studied in open-label trials and did not improve the lethargy / social withdrawal subscale of the Aberrant Behavioral Checklist (Ichikawa et al., Child Psychiatry Hum. Dev. 2017, 48:796-806; LeClerc et al., Pharma. Ther. 2015, 40:389-397; Posey et al., Child Adolesc. Psychiatry Clin. N. Am. 2008, 17:787-798). Studies with risperidone suggest that risperidone may produce modest improvements in core symptoms in children with pervasive developmental disorders who exhibit high levels of baseline irritability, but it is unclear whether risperidone improves these symptoms in the absence of irritability (LeClerc et al., Pharma. Ther. 2015, 40:389-397; Posey et al., Child Adolesc. Psychiatry Clin. N. Am. 2008, 17:787-798). Therefore, there is no support from human studies for the utility of aripiprazole for treating social communication dysfunction in ASD. Risperidone also lacks solid evidence of its effectiveness in improving social behavior in subjects with ASD.

[0008] The pharmacodynamic effects of risperidone and aripiprazole have also been studied in animal models of autism, with mixed results. Neither aripiprazole nor risperidone improved social behavior deficits in many preclinical mouse models of ASD, including the prenatal valproate model (Auclair et al., World Congress of The International College of Neuropsychopharmacology 2014, LP-03-011), Cntnap2 knockout mice (Penagarikano et al., Cell 2011, 147:235-246), NMDA receptor NR1 subunit hypomorphic mice (Teng et al., Neuropharmacology 2016, 105:61-71), and the BTBR mouse strain (Chadman, Pharm. Biochem. Behav. 2011, 97:586-594). In another study using prenatal valproate treatment in mice, both risperidone and aripiprazole improved core behavioral deficits after chronic administration, whereas acute treatment had no effect (Hara et al., Psychopharmacology 2017, 234:3217-3228). Hara et al. discussed the possible mechanisms behind the improvement of ASD-like symptoms resulting from long-term risperidone and aripiprazole treatment, emphasizing the role of dopamine D1 and D2 receptor activation following dopamine release in the prefrontal cortex. Hara et al. did not address the role of dopamine D3 receptors in the molecular mechanisms by which risperidone or aripiprazole may attenuate the behavioral effects of prenatal valproate treatment.

[0009] WO2005 / 012266A1 discloses carbamoylcyclohexane derivatives that are partial agonists of the dopamine D3 / D2 receptor. WO2005 / 012266A1 discloses, in particular, trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea (cariprazine) and its hydrochloride salt, which correspond to formula 1. As later established, cariprazine (USA: Vraylar®, Europe: Reagila®) is a serotonin receptor agonist that activates dopamine D3, preferably D3 / D2, receptors, and serotonin 5-HT 1A It is a partial agonist of the receptor (Kiss et al., J. Pharmacol. Exp. Therap. 2010, 333: 328-340) and is approved for the treatment of schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Active metabolites of cariprazine include, but are not limited to, desmethylcariprazine and didesmethylcariprazine (WO2008 / 142461A1). Further patent applications have described cariprazine hydrochloride (WO2008 / 139235A2) and deuterated derivatives of cariprazine (WO2011 / 060363A2).

[0010] WO 2005 / 012266 A1 also discloses closely related analogs of cariprazine, which are listed on pages 21 and 22 of the patent application, including trans-N-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-morpholine-4-carboxamide (Compound 2). [ka]

[0011] Among the diseases treated and / or prevented by carbamoylcyclohexane derivatives, the claims of WO2005 / 012266A1, WO2008 / 139235A2, WO2008 / 141135A1, WO2009 / 020897A1, and WO2010 / 009309A1 describe the treatment of autism and other conditions. As mentioned above, ASD is a highly complex disorder in terms of symptoms in human patients, and its core symptoms include social communication dysfunction and variable severity of restricted / repetitive behaviors, as well as a wide variety of comorbid conditions. Selected ASD-related symptoms, as defined herein below, were not identified or supported by any scientific evidence in the aforementioned patent applications. These symptoms specifically include social communication dysfunction, restricted and repetitive behaviors, attention deficit and hyperactivity, and irritability.

[0012] Compared to risperidone and aripiprazole, cariprazine has a unique receptor profile (Shahid et al., J. Psychopharmacol. 2009, 23:65-73; Kiss et al., J. Pharmacol. Exp. Therap. 2010, 333:328-340). Cariprazine binds to dopamine D3, D 2L and D 2S It exhibits subnanomolar affinity for the receptors (Ki values ​​of 0.09, 0.5, and 0.7 nM, respectively) and has approximately an eight-fold preference for dopamine D3 versus D2 receptors. Functionally, the compound is a partial agonist at dopamine D3 and D2 receptors. In addition, cariprazine inhibits serotonin 5-HT 2B and 5-HT 1A They exhibit nanomolar affinities (Ki of 0.6 and 2.6 nM, respectively) at the receptor (acting as full and weak partial agonists). A closely related analog of cariprazine (compound 2) exhibits a molecular pharmacological profile very similar to that of cariprazine. This compound also inhibits dopamine D3, D 2L and D 2SIt has subnanomolar affinity for the receptors (Ki of 0.17, 0.4, and 0.52 nM, respectively). Functionally, Compound 2 is a partial agonist at dopamine D3 and D2 receptors. In addition, Compound 2 inhibits the serotonin 5-HT 2B and 5-HT 1A They exhibit nanomolar affinities (Ki of 1.11 and 5.73 nM, respectively) at the receptor (acting as full and weak partial agonists). This combination of receptor affinity and functionality makes cariprazine and its closely related analogue (compound 2) unique and distinct from other available antipsychotic drugs.

[0013] Although the results of genetic association studies available at the time (Martineau et al., Dev. Med. Child Neurol. 1994, 36:688-697; Persico and Napolioni, Behav. Brain Res. 2013, 251:95-112) did not implicate the dopamine D3 receptor in the pathological mechanisms of ASD, researchers at Pierre Fabre Medicament were the first to study a dopamine D3 receptor antagonist and found it to be effective in animal models of ASD. Pierre Fabre Medicament filed a patent application (WO 2015 / 086836 A1) for chromone derivatives for their use as pharmaceuticals for the treatment of ASD. The chromone derivative in WO 2015 / 086836 A1 is a full antagonist of the dopamine D3 receptor, lacking intrinsic activity as revealed by MAP kinase activity testing against human recombinant dopamine D3 receptors. The chromone derivatives of this invention have been shown to improve impaired social behavior in rats exposed to sodium valproate during their intrauterine life. Despite their beneficial effects in the above animal models of ASD, there is no clinical evidence available to date that the chromone compounds disclosed in patent application WO2015 / 086836A1 or related compounds are useful for the treatment of this disorder in human patients.

[0014] Cariprazine is a partial agonist at dopamine D2 and D3 receptors (Kiss et al., J. Pharmacol. Exp. Therap. 2010, 333:328-340; Tadori et al. Eur. J. Pharmacol. 2011, 668:355-365), whereas according to WO2015 / 086836A1, the chromone derivatives according to the Pierre Fabre Medicament patent are defined as dopamine D3 antagonists, and therefore, a person skilled in the art would not expect the two compounds to have similar effects.

[0015] First, there are clear differences in chemical structure between the two basic compounds, which leads to differences in physicochemical, molecular pharmacological, pharmacodynamic and pharmacokinetic properties.

[0016] Second, Pierre Fabre's compound did not produce stimulatory activity in cell lines (ERK1 / 2 phosphorylation assay) (Heusler et al., Eur. Neuropsychopharm. 2016, 26(S2):S490-S491), whereas cariprazine stimulated ERK1 / 2 phosphorylation in Chinese hamster ovary cells expressing D3 receptors (unpublished data, data on company files), suggesting that the two compounds behave completely differently in in vitro functional assays.

[0017] Third, the two compounds have different receptor profiles (Heusler et al., Eur. Neuropsychopharm. 2016, 26(S2):S490-S491; Kiss et al., J. Pharmacol. Exp. Therap. 2010, 333:328-340). Pierre Fabre's chromone derivative has subnanomolar affinity for the dopamine D3 receptor (Ki of 0.16 nM), and dopamine D 2L and D 2SThey have nanomolar affinities for the receptors (Ki 12.6 and 6.3 nM, respectively). Thus, Pierre Fabre's compound has a greater preference for dopamine D3 versus D2 receptors than cariprazine. Chromone derivatives exert significant serotonin 5-HT 1A Cariprazine, its close analogue (compound 2), and Pierre Fabre's compound all inhibit the serotonin 5-HT receptor. 1A Although partial agonists of the receptor, Pierre Fabre's chromone derivatives have considerable intrinsic activity (57-75%) (Heusler et al., Eur. Neuropsychopharm. 2016, 26(S2):S490-S491), whereas cariprazine and Compound 2 are only weak partial agonists with intrinsic activities of 38% and 30%, respectively (Kiss et al., J. Pharmacol. Exp. Therap. 2010, 333:328-340, and unpublished data, company files).

[0018] As mentioned above, cariprazine has partial agonism of dopamine D3 / D2 receptors and weak serotonin 5-HT 1A Partial agonism of the receptor, and serotonin 5-HT 2B Lim et al. 2B They found that treatment with the receptor agonist BW723C86 resulted in improved cognitive performance (Lim et al., Gene. Dev. 2014, 28:273-289). Further research has reported that ASD patients also experience reduced function of serotonin 5-HT2 type (unspecified) receptors in the periphery and brain (McBride et al., Arch. Gen. Psychiatry 1989, 46, 213-221). Considering the above results, it is likely that serotonin 5-HT receptors such as cariprazine may be effective in treating ASD patients. 2BIt is not predicted that receptor antagonists will be effective in animal models of ASD.

[0019] Furthermore, Oblak et al. (Autism Res. 2013, 6:571-583) reported that serotonin 5-HT2+ was elevated in postmortem cortical samples from subjects with autism in two regions of the limbic-cortical network that contribute to socio-emotional behavior. 1A These decreased serotonin 5-HT receptor binding. 1A Given the receptor levels, it is unlikely that a weak partial agonist such as cariprazine at these receptors would be effective in an ASD model.

[0020] There is a need to treat autism generally, as well as to treat one or more symptoms of autism, and there is also a need to treat conditions such as Asperger's syndrome, atypical autism (also known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD), and sensory integration disorder. Summary of the Invention

[0021] In one aspect, this application relates to trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea (cariprazine), its salts, close analogs, derivatives, pharmaceutical compositions, metabolites, and combinations for use in treating symptoms of autism spectrum disorder. In another aspect, this application relates to the use of cariprazine, its salts, close analogs, derivatives, pharmaceutical compositions, metabolites, and combinations for the treatment of a condition selected from Asperger's syndrome, atypical autism (also known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD), pathological demand avoidance (PDA), fragile X syndrome (FXS), Angelman syndrome, tuberous sclerosis complex, Phelan-McDermid syndrome, and sensory integration disorder. DETAILED DESCRIPTION OF THE INVENTION

[0022] In one aspect, the present application relates to trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) and trans-N-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-morpholine-4-carboxamide hydrochloride (Compound 2), as disclosed in WO 2005 / 012266 A1. Cariprazine has demonstrated significant benefit in animal models for symptoms of ASD. These results indicate that cariprazine, its closely related analogs, and derivatives thereof may have potential therapeutic use for symptoms of ASD in human patients.

[0023] In one aspect, the application relates to the use of cariprazine, its salts, close analogs, derivatives, pharmaceutical compositions, metabolites, and combinations, for the treatment of a condition selected from Asperger's syndrome, atypical autism (also known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD), pathological demand avoidance (PDA), fragile X syndrome (FXS), Angelman syndrome, tuberous sclerosis complex, Phelan-McDermid syndrome, and sensory integration disorder.

[0024] In preferred embodiments, cariprazine or a pharmaceutically acceptable salt thereof is used for the treatment of persistent deficits in social communication and social interaction associated with ASD; for the treatment of restricted or repetitive behaviors associated with ASD; for the treatment of stereotyped or repetitive movements associated with ASD; and / or as a treatment for deficits in social-emotional interactions associated with ASD.

[0025] In a preferred embodiment, cariprazine or a pharmaceutically acceptable salt thereof is used to treat one or more symptoms of ASD selected from social communication deficits, restricted interests, and repetitive behaviors. In some embodiments, cariprazine or a pharmaceutically acceptable salt thereof is used to treat one or more symptoms of ASD selected from restricted, repetitive, and stereotyped patterns of behavior, interests, and activities.

[0026] Cariprazine and Compound 2 were studied in a prenatal valproate model of ASD. As described in the Examples, cariprazine hydrochloride and Compound 2 hydrochloride were able to reverse behavioral deficits in rats exposed to valproate during their intrauterine life. The results indicate that these two compounds are suitable for treating symptoms of ASD.

[0027] In another preferred embodiment, the present application is directed to the use of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or its close analogs, and / or its derivatives, and / or its metabolites, and / or its pharmaceutically acceptable salts, for the treatment of social communication deficits as a core symptom of autism spectrum disorder.

[0028] In another preferred embodiment, the present application is directed to the use of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or its close analogs, and / or its derivatives, and / or its metabolites, and / or its pharmaceutically acceptable salts, for the treatment of restrictive and repetitive behaviors as a core symptom of autism spectrum disorder.

[0029] In another preferred embodiment, the present application is directed to the use of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or its close analogs, and / or its derivatives, and / or its metabolites, and / or its pharmaceutically acceptable salts, for the treatment of irritability associated with autism spectrum disorder.

[0030] In another preferred embodiment, the present application is directed to the use of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or its close analogs, and / or its derivatives, and / or its metabolites, and / or its pharmaceutically acceptable salts, for the treatment of attention deficit and hyperactivity associated with autism spectrum disorder.

[0031] In another preferred embodiment, the present application relates to a pharmaceutical composition as defined above, wherein a core symptom of autism spectrum disorder is a deficit in social communication.

[0032] In another preferred embodiment, the present application relates to a pharmaceutical composition as defined above, wherein the core symptom of autism spectrum disorder is restricted and repetitive behaviors.

[0033] In another preferred embodiment, the present application relates to a pharmaceutical composition as defined above, wherein the condition to be treated is irritability associated with autism spectrum disorder.

[0034] In another preferred embodiment, the present application relates to a pharmaceutical composition as defined above, wherein the condition to be treated is attention deficit and hyperactivity associated with autism spectrum disorder.

[0035] The present application also relates to a method for treating autism spectrum disorders, comprising the administration of a pharmaceutical composition as defined above.

[0036] The compositions of the present application can be administered orally, transdermally, parenterally, intranasally, and rectally. The compositions, particularly in appropriate formulations, can be administered orally. The dosage of the compound (trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea) or its closely related analogs, salts, derivatives, or metabolites in the compositions of the present application can be adjusted to obtain an amount of active substance that produces the desired therapeutic response. Accordingly, dosage levels depend on the desired therapeutic response, the route of administration, the expected duration of treatment, and other factors such as the patient's age, sex, or weight. Dosages can range from 0.01 to 12 mg daily and can be titrated upward for efficacy.

[0037] Cariprazine may also be used in combination with at least one other active ingredient (e.g., a psychostimulant, antipsychotic, antidepressant, anxiolytic, antihypertensive, antiepileptic, narcotic, anticonvulsant, or other agent) already used for the treatment of comorbid symptoms of ASD.

[0038] Psychostimulants include, but are not limited to, centrally acting sympathomimetics (amphetamine, methylphenidate, modafinil, atomoxetine), nootropics, or other psychostimulants (vinpocetine, donepezil, memantine).

[0039] Antipsychotics include typical and atypical antipsychotics such as, but not limited to, haloperidol, pimozide, clozapine, olanzapine, quetiapine, sertindole, ziprasidone, lurasidone, risperidone, aripiprazole, brexpiprazole, iloperidone, paliperidone, lithium, and the like.

[0040] Antidepressants include, but are not limited to, nonselective monoamine reuptake inhibitors (desipramine, imipramine, clomipramine, amitriptyline, nortriptyline), serotonin modulators and stimulants (vilazodone, vortioxetine), selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram), non-hydrazide monoamine oxidase inhibitors (moclobemide), or other agents (mianserin, trazodone, nefazodone, mirtazapine, tianeptine, venlafaxine, milnacipran, reboxetine, duloxetine, agomelatine, bupropion, gepirone).

[0041] Anti-anxiety medications include, but are not limited to, benzodiazepines (diazepam, chlorodiazepoxide, oxazepam, lorazepam, alprazolam), azaspirodedione (buspirone).

[0042] Antihypertensive agents include, but are not limited to, imidazoline receptor agonists (clonidine, guanfacine) and combinations of these agents with diuretics.

[0043] Antiepileptic drugs include, but are not limited to, barbiturates and their derivatives (phenobarbital), hydantoin derivatives (phenytoin), succinimide derivatives (ethosuximide), the benzodiazepine derivative clonazepam, carboxamide derivatives (carbamazepine, oxcarbazepine), fatty acid derivatives (valproic acid, valpromide, vigabatrin, tiagabine), and other antiepileptic drugs (lamotrigine, topiramate, gabapentin, levetiracetam, zonisamide, pregabalin).

[0044] Narcotics include, but are not limited to, barbiturates (pentobarbital), benzodiazepines (midazolam), cyclopyrrolones, benzodiazepine derivatives (zopiclone, zolpidem), and melatonin receptor agonists (melatonin, ramelteon).

[0045] Antispasmodic or anticonvulsant drugs include, but are not limited to, centrally acting agents (baclofen, arbaclofen, tolperisone), and papaverine.

[0046] Other agents include, but are not limited to, pharmaceuticals (probiotics, digestive aids / digestive medicines, herbal extracts), vitamins (both water-soluble and fat-soluble, for example, but not limited to, vitamins A, D3, E, K, B1, B5, B6, B12, C, or derivatives thereof), and nutritional supplements (coenzymes, e.g., Q10, flavonoids, e.g., resveratrol, lecithin, unsaturated fatty acids, including omega-3 and omega-6 fatty acids).

[0047] Accordingly, the present invention also provides a pharmaceutical composition for use in the treatment of an autism spectrum disorder, comprising: 1) trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or its closely related analogs, and / or its derivatives, and / or its metabolites, and / or its pharmaceutically acceptable salts; 2) at least one adjunctive therapeutic agent selected from the group consisting of psychostimulants / nootropics, antipsychotics, antidepressants, anxiolytics, antihypertensives, antiepileptics, narcotics, and anticonvulsants; 3) one or more pharmaceutically acceptable carriers, diluents and excipients; The present invention relates to a pharmaceutical composition comprising:

[0048] At the same time, the present application also relates to a pharmaceutical combination comprising trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or its close analogs, and / or its derivatives, and / or its metabolites, and / or its pharmaceutically acceptable salts, and at least one adjunctive therapeutic agent for use in the treatment of autism spectrum disorders.

[0049] In a preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein at least one adjunctive therapeutic agent is selected from the group consisting of psychostimulants / nootropics, antipsychotics, antidepressants, anxiolytics, antihypertensives, antiepileptics, narcotics and anticonvulsants.

[0050] In another preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein the psychostimulant / nootropic is selected from the list comprising amphetamine, methylphenidate, modafinil, atomoxetine, vinpocetine, donepezil and memantine.

[0051] In another preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein the antipsychotic drug is selected from the list comprising haloperidol, pimozide, clozapine, olanzapine, quetiapine, sertindole, ziprasidone, lurasidone, risperidone, aripiprazole, brexpiprazole, iloperidone, paliperidone and lithium.

[0052] In another preferred embodiment, the application relates to a pharmaceutical combination as defined above, wherein the antidepressant is selected from the list comprising desipramine, imipramine, clomipramine, amitriptyline, nortriptyline, vilazodone, vortioxetine, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram-moclobemide, mianserin, trazodone, nefazodone, mirtazapine, tianeptine, venlafaxine, milnacipran, reboxetine, duloxetine, agomelatine, bupropion and gepirone.

[0053] In another preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein the anxiolytic is selected from the list comprising diazepam, chlorodiazepoxide, oxazepam, lorazepam, alprazolam and buspirone.

[0054] In another preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein the antihypertensive drug is selected from clonidine and guanfacine.

[0055] In another preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein the antiepileptic drug is selected from the list comprising phenobarbital, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, valpromide, vigabatrin, tiagabine, lamotrigine, topiramate, gabapentin, levetiracetam, zonisamide and pregabalin.

[0056] In another preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein the narcotic is selected from the list comprising pentobarbital, midazolam, zopiclone, zolpidem, melatonin and ramelteon.

[0057] In another preferred embodiment, the present application relates to a pharmaceutical combination as defined above, wherein the antispasmodic drug is selected from the list comprising baclofen, arbaclofen, tolperisone and papaverine.

[0058] In one embodiment, cariprazine or a pharmaceutically acceptable salt thereof is used to treat a pediatric patient between about 5 and 12 years of age, or an adolescent patient between about 13 and 17 years of age, or an adult patient about 18 years of age or older.

[0059] Preparation of Pharmaceutical Compositions The following formulation examples illustrate representative pharmaceutical compositions of the present application. A. Solid Oral Dosage Forms Tablets b. Capsules c. Granules B. Liquid Oral Dosage Forms a. Syrup C. Other dosage forms a. Suppositories b. Transdermal patch c. Nasal sprays, aerosols

[0060] definition The term "affinity" refers to the attraction of a drug for a biological target and is a chemical term used to quantify the strength of a drug-target interaction.

[0061] The term "full agonist" refers to a compound that produces the full maximal response of a biological system.

[0062] The term "partial agonist" refers to a compound that associates with a receptor and has only partial efficacy at the receptor compared to a full agonist.

[0063] The term "antagonist" refers to a compound that associates with a receptor and produces no response or blocks the response produced by an agonist of the same receptor.

[0064] The term "close analogues" refers to a group of compounds related to a compound on the basis of the similarity of their chemical structure and their in vitro pharmacological profiles.

[0065] The term "salts" refers to the non-toxic base addition salts of compounds of the present invention, which are typically prepared by reacting an acid with a suitable organic or inorganic base.

[0066] The term "active metabolite" refers to a metabolite produced by a different pathway of biotransformation that has a biological activity similar to that of the parent compound.

[0067] The term "derivatives" refers to compounds produced by chemical modification of cariprazine and its closely related analogs, including, but not limited to, prodrugs, deuterated compounds, bioisosteres, and the like.

[0068] The term "active ingredient" means cariprazine, its close analogs, salts, active metabolites and derivatives.

[0069] The term "pharmaceutically acceptable" refers to ingredients that are useful in preparing pharmaceutical compositions and that are generally safe, non-toxic, and not biologically or non-biologically undesirable, including those that are acceptable for human pharmaceutical use.

[0070] The term "pharmaceutical composition" refers to a mixture of a compound of the present invention with other chemical components, such as a pharmaceutically acceptable excipient, e.g., a diluent or carrier. A pharmaceutical composition facilitates administration of the compound to a subject.

[0071] The term "excipient" refers to a chemical that facilitates the uptake of a compound into cells or tissues.

[0072] "Core symptoms" include social-communicative dysfunction and restrictive (repetitive, stereotyped) behaviors and thoughts, as described in the Diagnostic and Statistical Manual of Mental Disorders, 15th Edition (2013).

[0073] The term "comorbid conditions" refers to conditions that may be associated with ASD but are not core conditions according to the Diagnostic and Statistical Manual of Mental Disorders, 15th Edition (2013).

[0074] As used herein, the term "treatment" refers to the use of an effective therapy to reduce, alleviate, or eliminate symptoms associated with ASD.

[0075] The term "patient" refers to a human who has been diagnosed with ASD.

[0076] Prenatal valproate model Prenatal exposure to valproate (valproic acid, VPA) is known to increase the risk of ASD in humans (Christensen et al., JAMA 2013, 309). VPA exposure during intrauterine life in rodents is also known to result in autism-like phenotypes in offspring (Roullet et al., Neurotox. Teratol. 2013, 36, 45-56). In rodents, VPA is typically administered around embryonic day 12, when neural tube closure and establishment of cranial nerve nuclei and the cerebellum occur. VPA's histone deacetylase inhibitory effects disrupt these developmental stages, thereby causing autism-like phenotypes in offspring. Autism-like phenotypes include, but are not limited to, impaired communication in pups, impaired social play behavior, hyperactivity, excessive stereotypy in adolescent rats, and social deficits in the three-chamber assay in adult rats. Because the physiological origins and symptoms of the prenatal VPA model show good agreement with the human pathology, the prenatal VPA model is a widely accepted rodent model of ASD with high translational value.

[0077] As described above, the prenatal VPA model has excellent construct and face validity and is therefore a widely accepted disease model of ASD. In this method, time-matched female Wistar rats are administered a single dose of VPA (300–600 mg / kg, i.p.) on day 12.5 of gestation. The offspring are housed under standard experimental conditions until the time of behavioral testing. Animals are housed in groups of four in conventional cages, with free access to food and water, maintained at 22–24°C under a standard 12-h light / dark cycle. After treatment with the investigational drug, the offspring are behaviorally examined using tests suitable for assessing autistic behaviors. These tests include maternal deprivation-induced ultrasonic vocalizations, social play, social preference, and open field testing in rat pups.

[0078] Maternal deprivation-induced ultrasonic vocalizations in rat pups are a measure of impaired social communication function in offspring after prenatal exposure to VPA (Gandal et al., Biol. Psychiatry 2010, 68, 1100-1106). To induce ultrasonic calls, prenatally VPA-treated rat pups are individually placed in cages where calls are recorded with a bat microphone. Calls are digitized with an audio filter, and ultrasonic vocalizations are recorded and quantified using SonoTrack software (Metris bv, The Netherlands). Baseline vocalizations are measured for 10 min on postnatal days 11-12. Animals are divided into homogenous groups based on baseline vocalizations. On postnatal day 13, animals are treated with the appropriate dose of drug or vehicle po 60 min before measurement and then returned to their home location until recording. Ultrasonic call counts are recorded for 10 min. Statistical analysis will be performed on ultrasound call counts using the non-parametric Kruskal-Wallis test and post-hoc Dunnett's test.

[0079] Social play is a highly typical type of social interaction in adolescent mammals, including rodents and humans (Vanderschuren and Trezza, Curr. Topics Behav. Neurosci. 2014, 16:189-212). Social play behavior, indicative of adult social function, is impaired after prenatal VPA treatment in offspring (Schneider and Przewlocki, Neuropsychopharmacology 2005, 30:80-89). On postnatal day 30, after 8 days of treatment with test compounds, prenatal VPA-treated rats are assessed for juvenile play behavior. Testing is conducted in a novel testing arena with pairs of animals from the same treatment group over a 15-minute test. Animals are scored for play activity, measured by the duration of social play behavior. Statistical analysis uses one-way analysis of variance and post-hoc Dunnett's test.

[0080] Social preference in a three-chamber apparatus is another indicator of intact social behavior in rats. The preference for conspecifics over inanimate objects and the ability to distinguish between familiar and novel conspecifics are necessary for normal social function and are impaired in the prenatal VPA model in rats (Bambini-Junior et al., Brain Res. 2011, 1408:8-16). Social preference and social recognition memory are studied in a three-chamber apparatus. On postnatal day 59, prenatal VPA-treated rats are assessed for their social preference after 8 days of oral treatment with test compounds. On postnatal day 60, the same rats are assessed for their social recognition memory after 9 days of oral treatment with test compounds. Statistical analysis is performed using two-way analysis of variance, Student's t-test, and Dunnett's test.

[0081] In addition to social-communicative dysfunction, repetitive behaviors are another core symptom area of ​​ASD. Hyperactivity and excessively repetitive behaviors are observed in animals exposed to VPA during intrauterine life (Schneider and Przewlocki Neuropsychopharmacology 2005, 30:80-89). On postnatal days 31-32, animals are scored for locomotor activity and exploratory behavior in a 10-minute test in the activity arena of an open field test after 9 days of oral treatment with the test compound. Activity is analyzed for repetitive / stereotypic behavioral measures, such as total distance traveled and frequency of circling. Statistical analysis is performed using one-way analysis of variance and post-hoc Dunnett's test. [Brief explanation of the drawings]

[0082] [Figure 1]Acute oral administration of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) reversed the social communication deficits induced by prenatal valproate treatment (### p<0.001; Dunnett's multiple comparison test for "VPA+VEH"). The effect of cariprazine was statistically significant at doses of 0.003, 0.03, and 0.1 mg / kg (*, ** p<0.05, <0.01; Dunnett's test for "VPA+VEH"). VEH+VEH refers to prenatal vehicle treatment combined with vehicle treatment before behavioral testing. VPA+VEH animals received prenatal VPA combined with vehicle treatment before behavioral testing. The VPA+CAR / 0.003, CAR / 0.01, CAR / 0.03, and CAR / 0.1 groups received prenatal VPA followed by 0.003, 0.01, 0.03, and 0.1 mg / kg cariprazine, respectively. [Figure 2] Acute oral administration of trans-N-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-morpholine-4-carboxamide hydrochloride (Compound 2) reversed the social communication deficits induced by prenatal valproate treatment (### p<0.001; Dunnett's multiple comparison test for "VPA+VEH"). The effect of Compound 2 was statistically significant at both doses tested (* p<0.05; Dunnett's test for "VPA+VEH"). VEH+VEH refers to prenatal vehicle treatment combined with vehicle treatment prior to behavioral testing. VPA+VEH animals received prenatal VPA combined with vehicle treatment prior to behavioral testing. The VPA+Compound 2 / 0.002 and Compound 2 / 0.2 groups received prenatal VPA followed by 0.002 and 0.2 mg / kg Compound 2, respectively. [Figure 3]Repeated (8 days of daily treatment) oral administration of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) reversed the social play deficits induced by prenatal valproate treatment. The effect of cariprazine was statistically significant at the 0.1 mg / kg dose (*p<0.05; Dunnett's test for "VPA+VEH"). VEH+VEH refers to prenatal vehicle treatment combined with vehicle treatment prior to behavioral testing. VPA+VEH animals received prenatal VPA combined with vehicle treatment prior to behavioral testing. The VPA+CAR / 0.003, CAR / 0.01, CAR / 0.03, and CAR / 0.1 groups received prenatal VPA followed by 0.003, 0.01, 0.03, and 0.1 mg / kg cariprazine, respectively. [Figure 4] Repeated (9 days of daily treatment) oral administration of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) reversed the hyperactivity induced by prenatal valproate treatment. The effect of cariprazine was statistically significant at a dose of 0.1 mg / kg (*p<0.05; Dunnett's test for "VPA+VEH"). VEH+VEH refers to prenatal vehicle treatment combined with vehicle treatment before behavioral testing. VPA+VEH animals received prenatal VPA combined with vehicle treatment before behavioral testing. The VPA+CAR / 0.003, CAR / 0.01, CAR / 0.03, and CAR / 0.1 groups received prenatal VPA followed by 0.003, 0.01, 0.03, and 0.1 mg / kg cariprazine, respectively. [Figure 5]Repeated (9 days of daily treatment) oral administration of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) reversed the excessive circling behavior induced by prenatal valproate treatment. The effect of cariprazine was statistically significant at all doses (*p<0.05; Dunnett's test for "VPA+VEH"). VEH+VEH refers to prenatal vehicle treatment combined with vehicle treatment before behavioral testing. VPA+VEH animals received prenatal VPA combined with vehicle treatment before behavioral testing. The VPA+CAR / 0.003, CAR / 0.01, CAR / 0.03, and CAR / 0.1 groups received prenatal VPA followed by 0.003, 0.01, 0.03, and 0.1 mg / kg cariprazine, respectively. [Figure 6] Repeated (daily treatment for 8 days) oral administration of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) reversed the social preference deficit induced by prenatal valproate treatment. The effect of cariprazine was statistically significant at the 0.1 mg / kg dose (*p<0.05; Dunnett's test for "VPA+VEH"). VEH+VEH refers to prenatal vehicle treatment combined with vehicle treatment prior to behavioral testing. VPA+VEH animals received prenatal VPA combined with vehicle treatment prior to behavioral testing. The VPA+CAR / 0.003, CAR / 0.01, CAR / 0.03, and CAR / 0.1 groups received prenatal VPA followed by 0.003, 0.01, 0.03, and 0.1 mg / kg cariprazine, respectively. [Example]

[0083] The following examples illustrate the invention without limiting its scope.

[0084] Example 1 Trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) was tested on pup communication in prenatally valproate-treated rats. Ultrasonic vocalizations (USVs) were induced by maternal deprivation. The effects of acute cariprazine administration on pup communication are shown in Figure 1. Data presented are the mean number of USVs ± SEM for 13–24 pups (including both male and female pups) per group. Oral cariprazine at doses of 0.003, 0.03, and 0.1 mg / kg increased and completely reversed isolation-induced vocalizations in valproate-treated pups. Therefore, cariprazine was able to reduce the social communication deficits induced by prenatal valproate treatment.

[0085] Example 2 Trans-N-(4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-morpholine-4-carboxamide hydrochloride (Compound 2) was tested on pup communication in prenatally valproate-treated rats. Ultrasonic vocalizations (USVs) in rat pups were induced by maternal deprivation. The effects of acute oral administration of Compound 2 on pup communication are shown in Figure 2. Data presented are the mean number of USVs ± SEM for 13–24 rat pups (which included both male and female pups) per group. Orally administered Compound 2 increased and completely reversed isolation-induced vocalizations in valproate-treated pups at each dose tested. Thus, Compound 2 was able to reduce the social communication deficits induced by prenatal valproate treatment.

[0086] Example 3 Trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) was tested on social play behavior in rats treated with prenatal valproate. The effects of repeated administration of cariprazine are shown in Figure 3. Data presented are the mean time spent playing ± SEM for four rat pairs (only male pups were tested) for each group. Orally administered cariprazine increased, but partially, significantly reversed, the social play deficits induced by prenatal valproate treatment. Thus, cariprazine was able to reduce the social communication deficits induced by prenatal valproate treatment.

[0087] Example 4 Trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) was tested on rat locomotion in an open-field assay in prenatal valproate-treated rats. The effect of repeated administration of cariprazine is shown in Figure 4. Data presented are the mean distance traveled ± SEM of eight rats per group (only male pups were tested). Orally administered cariprazine reduced and completely reversed the hyperlocomotion induced by prenatal valproate treatment. Therefore, cariprazine was able to reduce the hyperactivity induced by prenatal valproate treatment.

[0088] Example 5 Trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) was tested on rat stereotypic behavior in an open-field assay in prenatally valproate-treated rats. The effect of repeated administration of cariprazine is shown in Figure 5. Data presented are the mean number of 360-degree turns ± SEM for eight rats per group (only male pups were tested). Orally administered cariprazine reduced and completely reversed the excessive circling behavior induced by prenatal valproate treatment. Therefore, cariprazine was able to reduce the stereotypic behavior induced by prenatal valproate treatment.

[0089] Example 6 Trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride (cariprazine) was tested on social preference behavior in rats in a three-chamber assay in prenatally valproate-treated rats. The effects of repeated administration of cariprazine are shown in Figure 6. Data presented are the mean time of social exploration ± SEM for eight rats per group (only male pups were tested). Orally administered cariprazine increased and almost completely reversed the social deficits induced by prenatal valproate treatment. Therefore, cariprazine was able to reduce the social communication deficits induced by prenatal valproate treatment.

Claims

1. trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or a closely related analogue thereof, and / or a derivative thereof, and / or a metabolite thereof, and / or a pharmaceutically acceptable salt thereof, for use in the treatment of autism spectrum disorder, wherein a core symptom of autism spectrum disorder is a deficit in social communication.

2. trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or a closely related analogue thereof, and / or a derivative thereof, and / or a metabolite thereof, and / or a pharmaceutically acceptable salt thereof, for use in the treatment of autism spectrum disorder, wherein a core symptom of autism spectrum disorder is restricted and repetitive behaviors.

3. trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or its close analogues, and / or its derivatives, and / or its metabolites, and / or its pharmaceutically acceptable salts, for use in the treatment of irritability associated with autism spectrum disorder, wherein the condition to be treated is autism spectrum disorder associated with irritability.

4. trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or a closely related analogue thereof, and / or a derivative thereof, and / or a metabolite thereof, and / or a pharmaceutically acceptable salt thereof, for use in the treatment of autism spectrum disorder, wherein the condition to be treated is autism spectrum disorder associated with attention deficit and hyperactivity.

5. Use of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or a closely related analog thereof, and / or a derivative thereof, and / or a metabolite thereof, and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of symptoms of autism spectrum disorder.

6. The use according to claim 5, wherein a core symptom of autism spectrum disorder is a deficit in social communication.

7. 6. The use according to claim 5, wherein the core symptom of autism spectrum disorder is restricted and repetitive behaviors.

8. 6. The use of claim 5, wherein the condition to be treated is irritability associated with autism spectrum disorder.

9. 6. The use of claim 5, wherein the condition to be treated is attention deficit and hyperactivity associated with autism spectrum disorder.

10. The use according to any one of claims 5 to 9, wherein trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea is in the form of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride.

11. The use according to any one of claims 5 to 9, wherein trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-morpholine-4-carboxamide is used.

12. The use according to any one of claims 5 to 9 and 11, wherein trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-morpholine-4carboxamide is in the form of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-morpholine-4carboxamide hydrochloride.

13. A pharmaceutical composition comprising trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or a closely related analog thereof, and / or a derivative thereof, and / or a metabolite thereof, and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in treating one or more core symptoms of autism spectrum disorder.

14. 14. The pharmaceutical composition for use according to claim 13, wherein the core symptom of autism spectrum disorder is a deficit in social communication.

15. 14. The pharmaceutical composition for use according to claim 13, wherein the core symptom of autism spectrum disorder is restricted and repetitive behaviors.

16. 14. The pharmaceutical composition for use according to claim 13, wherein the condition to be treated is irritability associated with autism spectrum disorder.

17. 14. The pharmaceutical composition for use according to claim 13, wherein the condition to be treated is attention deficit and hyperactivity associated with autism spectrum disorder.

18. A pharmaceutical combination comprising trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, and / or a closely related analogue thereof, and / or a derivative thereof, and / or a metabolite thereof, and / or a pharmaceutically acceptable salt thereof, and at least one adjunctive therapeutic agent for use in the treatment of autism spectrum disorder.

19. 19. The pharmaceutical combination of claim 18, wherein the at least one adjunctive therapeutic agent is selected from the group consisting of psychostimulants / cognitive enhancers, antipsychotics, antidepressants, anxiolytics, antihypertensives, antiepileptics, narcotics and anticonvulsants.

20. 20. The pharmaceutical combination of claim 19, wherein the psychostimulant / nootropic is selected from the group comprising amphetamine, methylphenidate, modafinil, atomoxetine, vinpocetine, donepezil and memantine.

21. 20. The pharmaceutical combination of claim 19, wherein the antipsychotic drug is selected from the group comprising haloperidol, pimozide, clozapine, olanzapine, quetiapine, sertindole, ziprasidone, lurasidone, risperidone, aripiprazole, brexpiprazole, iloperidone, paliperidone and lithium.

22. 20. The pharmaceutical combination of claim 19, wherein the antidepressant is selected from the group comprising desipramine, imipramine, clomipramine, amitriptyline, nortriptyline, vilazodone, vortioxetine, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram moclobemide, mianserin, trazodone, nefazodone, mirtazapine, tianeptine, venlafaxine, milnacipran, reboxetine, duloxetine, agomelatine, bupropion and gepirone.

23. 20. The pharmaceutical combination of claim 19, wherein the anti-anxiety drug is selected from the group comprising diazepam, chlordiazepoxide, oxazepam, lorazepam, alprazolam and buspirone.

24. 20. The pharmaceutical combination of claim 19, wherein the antihypertensive drug is selected from clonidine and guanfacine.

25. 20. The pharmaceutical combination of claim 19, wherein the antiepileptic drug is selected from the group comprising phenobarbital, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, valpromide, vigabatrin, tiagabine, lamotrigine, topiramate, gabapentin, levetiracetam, zonisamide and pregabalin.

26. 20. The pharmaceutical combination of claim 19, wherein the narcotic is selected from the group comprising pentobarbital, midazolam, zopiclone, zolpidem, melatonin and ramelteon.

27. 20. The pharmaceutical combination of claim 19, wherein the antispasmodic drug is selected from the group comprising baclofen, arbaclofen, tolperisone and papaverine.

28. 1. A method for treating a disease or disorder selected from Asperger's syndrome, atypical autism (also known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett's syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD), and sensory integration disorder, comprising administering to a patient in need of treatment a pharmaceutically effective amount of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea, or a pharmaceutical salt, ester, metabolite, or prodrug thereof.

29. 29. The method of claim 28, wherein the disease or disorder is Asperger's syndrome.

30. 29. The method of claim 28, wherein the disease or disorder is atypical autism.

31. 29. The method of claim 28, wherein the disease or disorder is Rett Syndrome.

32. 29. The method of claim 28, wherein the disease or disorder is childhood disintegrative disorder.

33. 29. The method of claim 28, wherein the disease or disorder is attention deficit hyperactivity disorder (ADHD).

34. 29. The method of claim 28, wherein the disease or disorder is a sensory integration disorder.

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