Carbamoyl cyclohexane derivatives for treating autism spectrum disorder

Abstract

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 in general, and preferably the object of the present invention is to treat one or more symptoms of autism.Furthermore, it was also found that cariprazine, its salts, close analogs, derivatives, pharmaceutical compositions, metabolites and combinations are suitable for 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.

1 .- 4 . (canceled) 
     
     
         5 . A method of treating one or more symptoms of autism spectrum disorder in a subject, comprising administering trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea and/or its active close analogs and/or its active derivatives and/or its active metabolites and/or pharmaceutically acceptable salts thereof to the subject. 
     
     
         6 . The method according to  claim 5  wherein the one or more symptoms of autism spectrum disorder are socio-communicational deficits. 
     
     
         7 . The method according to  claim 5 , wherein the one or more symptoms of autism spectrum disorder are restricted and repetitive behaviors. 
     
     
         8 . The method according to  claim 5 , wherein the one or more symptoms of autism spectrum disorder comprise is irritability. 
     
     
         9 . The method according to  claim 5 , wherein the one or more symptoms of autism spectrum disorder comprise attention deficit and hyperactivity. 
     
     
         10 . (canceled) 
     
     
         11 . The method according to  claim 35 , wherein the compound that is administered is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 11 , wherein the compound that is administered is the hydrochloride salt of 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 5 , wherein the trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea is further formulated as a pharmaceutical composition comprising trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea and/or its active close analogs and/or its active derivatives and/or its active metabolites and/or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. 
     
     
         14 .- 17 . (canceled) 
     
     
         18 . The method of  claim 5 , wherein the trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea and/or its active close analogs and/or its active derivatives and/or its active metabolites and/or pharmaceutically acceptable salts thereof is further administered in combination with at least one adjunctive therapeutic agent. 
     
     
         19 . The method according to  claim 18 , wherein the at least one adjunctive therapeutic agent is selected from the group consisting of psychostimulants/nootropics, antipsychotics, antidepressants, anxiolytics, antihypertensives, antiepileptics, narcotics, and spasmolytics. 
     
     
         20 . The method according to  claim 19 , wherein psychostimulants/nootropics are selected from the group consisting of amphetamine, methylphenidate, modafinil, atomoxetine, vinpocetine, donepezil and memantine. 
     
     
         21 . The method according to  claim 19 , wherein antipsychotics are selected from the group consisting of haloperidol, pimozide, clozapine, olanzapine, quetiapine, sertindole, ziprasidone, lurasidone, risperidone, aripiprazole, brexpiprazole, iloperidone, paliperidone and lithium. 
     
     
         22 . The method m according to  claim 19 , wherein antidepressants are selected from the group consisting of 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 . The method according to  claim 19 , wherein anxiolytics are selected from the group consisting of diazepam, chlorodiazepoxide, oxazepam, lorazepam, alprazolam and buspirone. 
     
     
         24 . The method according to  claim 19 , wherein antihypertensive is selected from clonidine and guanfacine. 
     
     
         25 . The method according to  claim 19 , wherein antiepileptics are selected from the group consisting of phenobarbital, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, valpromide, vigabatrin, tiagabine, lamotrigine, topiramate, gabapentin, levetiracetam, zonisamide and pregabalin. 
     
     
         26 . The method according to  claim 19 , wherein narcotics are selected from the group consisting of pentobarbital, midazolam, zopiclone, zolpidem, melatonin and ramelteon. 
     
     
         27 . (canceled) 
     
     
         28 . A method for treating a disease or disorder selected from Asperger's syndrome, atypical autism, Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD), and sensory integration dysfunction, comprising administering to a patient in need thereof a pharmaceutically effective amount of trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea or a pharmaceutically salt, or active metabolite thereof. 
     
     
         29 .- 32 . (canceled) 
     
     
         33 . The method according to  claim 28 , wherein said disease or disorder is attention deficit hyperactivity disorder (ADHD). 
     
     
         34 . (canceled) 
     
     
         35 . The method according to  claim 5 , wherein the compound that is administered is selected from the group consisting of: deuterated analogs of cariprazine, 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof.