US 20090318520A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0318520 A1 KOVacs et al. (43) Pub. Date: Dec. 24, 2009 (54) USE OF ISOINDOLES FOR THE TREATMENT Related U.S. Application Data OF NEUROBEHAVORAL DISORDERS (60) Provisional application No. 61/074,500, filed on Jun. 20, 2008. (75) Inventors: (US);Bruce Laura Kovacs, A. LongPinegar, Beach, Long CA PublicationO O Classification Beach, CA (US) (51) Int. Cl. A63L/488 (2006.01) Correspondence Address: (52) U.S. Cl. ........................................................ S14/393 BRCH STEWARTKOLASCH & BRCH (57) ABSTRACT PO BOX 747 FALLS CHURCH, VA 22040-0747 (US) The present invention generally relates to the use of drugs for the treatment of neurobehavioral disorders or symptoms of a neurobehavioral disorder associated with dysfunction of the (73) Assignee: Afecta Pharmaceuticals Drive, trimonoamine modulating system (TMMS). More specifi Irvine, CA (US) cally, the invention describes methods for the treatment of a neurobehavioral disorder and/or treatment or prevention of symptoms of a neurobehavioral disorder by administering (21) Appl. No.: 12/477,665 suitable Isoindole derivatives alone or in combination with other agents so as to provide relatively equal inhibitory effect (22) Filed: Jun. 3, 2009 on serotonin, dopamine and norepinephrine transporters. US 2009/03 18520 A1 Dec. 24, 2009 USE OF SONDOLES FOR THE TREATMENT 0005. The trimonoamine modulating system (TMMS), OF NEUROBEHAVORAL DISORDERS comprising the dopaminergic (DA), serotonergic (5 HT) and noradrenergic (NE) nuclei, modulate the activities of the five CROSS-REFERENCE TO RELATED basic circuitries note above (Othmer & Othmer et al., 1998). APPLICATIONS This occurs as a result of the modulatory effects of the TMMS 0001. The present application claims priority to prior U.S. on fast excitatory and inhibitory synaptic transmission in provisional application Ser. No. 61/074.500, filed on Jun. 20. these circuits. 2008, the entire contents of which are hereby incorporated by 0006 Fast synaptic transmission in the five basic nueronal reference. circuits is mediated by ligand gated ion channels. Glutamate (GLU), is the primary fast excitatory neurotransmitter of the TECHNICAL FIELD CNS, and gamma-amniobutyric acid (GABA) is the primary fast inhibitory neurottransmitter of the CNS. An important 0002 The present invention generally relates to the use of ligand gated ion channel active by glutamate is the NMDA drugs for the treatment of neurobehavioral disorders or symp receptor family, while the primary target of GABA is ligand toms of a neurobehavioral disorder associated with dysfunc gated chloride channel In contrast, all three monoamines tion of the trimonoamine modulating system (TMMS). More members of the TMMS (domamine, serotonin and norepi specifically, the invention describes methods for the treat nephrine) use G-protein coupled receptors and use second ment of a neurobehavioral disorder and/or treatment or pre messenger cytoplasmic pathways. Therefore, they can inter vention of symptoms of a neurobehavioral disorder by admin istering Suitable Isoindole derivatives alone or in combination act synergetically or antagonistically, depending on the sec with other agents so as to provide relatively equal inhibitory ondary messengers involved. For example, in the case of effect on serotonin, dopamine and norepinephrine transport noradrenaline and serotonin, depletion of one neurotransmit ter has little effect on patients treated with an antidepressant CS. acting primarily on the other neurotransmitter. Also in con trast to glutamate and GABA, the monoamines of the TMMS BACKGROUND OF THE INVENTION have a striking organization in the brain: the cell bodies pro 0003 Taken collectively, neurobehavioral disorders affect ducing the monoamines are restricted to a small number of a significant percentage of the population. These disorders nuclei, but their axons project widely throughout the nervous range from those conditions that first manifest in early child system. hood to those that occur exclusively in adults. Although clini 0007. Therefore, it is possible that the TMMS may act to cally they manifest with disparate symptomatology, the modulate fast synaptic transmission mediated by glutamate underlying etiology reflects dysfunction in one or more basic and gamma-amniobutyric acid through the extensive projec neuronal circuits in the central nervous system (CNS). Neu tions of their axons throughout the CNS. In support of this robehavioral disorders can be inherited or acquired and the concept is the fact that virtually all antidepressants reduce actual manifestation of the disorder is influenced by genetic ligand binding to glutamatergic NMDA receptors in the fron diatheses, the individual's environment and other circum tal cortex. Thus, modulation of NMDA receptor activation stances, such as physical changes. probably underlies the antidepressant action of both seroton 0004. Within the CNS, five basic functional neuronal cir ergic and noradrenergic reuptake inhibitors. In chronically cuits are described; the brainstem, the hypothalamic, the depressed patients, a reduction of glial cells in the Subgenual motor striatal, the limbic striatal and the neocortical striatal. prefrontal cortex (a small region connected to the hypothala All neurobehavioral disorders can be regarded as occurring mus and situated beneath the genua, or knee, of the corpus when one or more of these five brain circuits become dys callossum), has been Suspected to result in inadequate functional. From the perspective of the neuroanatomical sub glutamate transport leading to receptor activation. Similarly, strates all neurobehavioral disorders involve such structures GABAergic neurons, which constitute about 95% of the neu as: prefrontal cortex, cingulate cortex, entorhinal cortex, hip rons in the striatal complex area, form an inhibitory synaptic pocampus, nucleus accumbens (ventral striatum), Ventral pal network that is modulated by dopamine and perhaps other lidum, amygdala, and anterior hypothalamus (see Swanson monoamines. and Petrovich, 1998, Kalivas et al., 1993 and Heimer, 2003). 0008 Thus, drive-related activities mediated by the hypo Connections between these structures form the complex neu thalamus, emotional/motivational activities mediated by the ronal circuits noted above. Furthermore, projections between limbic circuitry and value-based behaviors, cognition in the structures are organized in a strict topographical manner (See neocortex circuitry as well as motor and reward based behav e.g. van Groen et al., 2002 and Heidbreder and Groenewegen, iors may all be modulated by the TMMS, through fine control 2003). The resulting functional macrostructure is primarily of the: brainstem, hypothalamic, motor-striatal, limbic-stri responsible for the generation and expression of motiva atal and the neocortical striatal circuits. Therefore, if there is tional, cognitive and affective states, as well as motor activity. dysfunction, imbalance or damage to the TMMS, the modu In addition, because of shared neurobiological Substrates latory effects could be altered and conversely, if the fast many primarily neurobehavioral disorders involve abnormal synaptic transmission in the five neuronal circuits is abnormal or involuntary movements such as those present in obsessive it could be corrected by manipulation of the TMMS through compulsive disorder, frontotemporal dementia, and attention simultaneous and differential alteration of the synaptic levels deficit-hyperactivity disorder. Similarly many disorders of the three monoamines; DA, 5 HT and NE. In addition, if which primarily manifest through abnormal motor function there is a dysfunction in the TMMS the deficient and/or Such as Tourette syndrome and Huntington's disease also abnormal modulation of the effected substrate CNS circuit have neurobehavioral, psychiatric and/or cognitive manifes ries would result in the clinical manifestation of various neu tations as well. robehavioral disorders. US 2009/03 18520 A1 Dec. 24, 2009 0009. As discovered by the inventors and disclosed herein, which, at the same time have a highly selective inhibitory many otherwise unrelated neurobehavioral disorders in effect on the serotonin transporter (SERT) as well as having a humans are associated with dysfunction of the TMMS. These highly selective inhibitory effect on the on the norepinephrine include: attention deficit disorder (ADD) attention deficit transporter (NET) such that the inhibitory effect as measured disorder with hyperactivity (ADHD), and other Pervasive by the Ki at each of these transporter is relatively equal (i.e. Developmental Disorders (such as Autism, Asperger's disor the Kiratio: DAT:SERT, DAT.NET, and SERT.NET is less der and Rett's syndrome), obsessive compulsive disorders than 50:1) show a unique effect in treating underlying dys (OCD), post traumatic stress disorder (PTSD), other Anxiety regulation various neuronal circuits and resulting neurobe Disorders (such as phobias and panic disorder), bipolar dis havioral disorders via action on the TMMS order, dysthymia and other mood disorders, Tourette Syn 0012. The consequence of this unique capacity results in drome and other movement disorders, Somatoform disorders an improved ability to treat individuals with a variety of like body dysmorphic disorder and substance abuse disor neurobehavioral disorders including two or more disorders ders. Heretofore, there has been no underlying common occurring at the