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(12) Patent Application Publication (10) Pub. No.: US 2016/0271141 A1 CHIPKIN (43) Pub US 20160271141A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0271141 A1 CHIPKIN (43) Pub. Date: Sep. 22, 2016 (54) FUSED BENZAZEPINES FOR TREATMENT Publication Classification OF STUTTERING (51) Int. Cl. (71) Applicant: PSYADON PHARMACEUTICALS, A6II 3/55 (2006.01) INC., Germantown, MD (US) A6II 45/06 (2006.01) A6IR 9/00 (2006.01) (72) Inventor: Richard E. CHIPKIN, Bethesda, MD (52) U.S. Cl. (US) CPC ............. A6 IK3I/55 (2013.01); A61K 9/0053 (73) Assignee: Psyadon Pharmaceuticals Inc. (2013.01); A61K 45/06 (2013.01) (21) Appl. No.: 15/030,271 (57) ABSTRACT (22) PCT Filed: Oct. 17, 2014 The present invention encompasses methods of treating a subject who stutters. The methods can include the steps of: (86). PCT No.: PCT/US2O14/06108O (a) identifying a subject in need of treatment; and (b) administering to the subject a therapeutically effective S 371 (c)(1), amount of a composition comprising a D1/D5 receptor (2) Date: Apr. 18, 2016 antagonist, a D1/D5 receptor partial agonist, or a mixture Related U.S. Application Data thereof. For example, the D1/D5 receptor antagonist can be ecopipam or a pharmaceutically acceptable salt, Solvate, (60) Provisional application No. 61/892.841, filed on Oct. hydrate, prodrug, structural analog, metabolite, or poly 18, 2013. morph thereof. US 2016/0271141 A1 Sep. 22, 2016 FUSED BENZAZEPINES FOR TREATMENT 0006. Several review articles concerning stuttering are OF STUTTERING available. These include: Boyd et al., J. Clin. Psychophar macol., 31:740–744, 2011; Ingham, et al., J. Fluency Dis CROSS-REFERENCE TO RELATED ord, 28:297-317, 2003; Maguire et al., Expert Opin. Phar APPLICATIONS macother, 5:1565-1571, 2004: Kraft and Yairi, Folia Phoniatrica et Logopaedica, 64:34-47; Ashert and Wasson, 0001. This application is a 371 National Phase of Inter Journal of American Osteopathic Association, 111:576-580; national Application No. PCT/US2014/061080, which was Newbury and Monaco, Neuron, 68:309-320; Prasse and filed on Oct. 17, 2014 and claims the benefit of the filing date Kikano, American Family Physician, 77:1271-1276, 2008: of U.S. Provisional Application No. 61/892,841, filed Oct. Bichel and Sommer, PLoS Biology, 2:159-163: Bothe et al., 18, 2013, the contents of each of which are hereby incor American Journal of Speech-Language Pathology, 15:321 porated by reference in their entirety. 341, 2005; Costa and Kroll, Canadian Medical Association Journal, 162:1849-1855, 2000; and Ashert and Wasson, FIELD OF THE INVENTION Journal of American Osteopathic Association, 111:576-580, 0002 This invention relates to methods of treating 2011). patients Suffering from Stuttering, and more particularly to the treatment of stuttering with fused benzazepines. SUMMARY 0007. The present invention is based, in part, on the use BACKGROUND of compounds that selectively bind the D1/D5 receptor and subsequently inhibit dopamine access to the D1/D5 receptor 0003. The International Classification of Diseases 2010 in the treatment of (e.g., the amelioration of) one or more of (ICD-10) defines stuttering, which is also called stammer the signs or symptoms associated with CSPT circuit disor ing, as “Speech that is characterized by frequent repetition ders. In one embodiment, the sign or symptom is Stuttering. or prolongation of Sounds or syllables or words, or by Accordingly, the present invention encompasses methods of frequent hesitations or pauses that disrupt the rhythmic flow treating a subject who stutters or stammers. The methods can of speech.” Stuttering is classified as a disorder when it include the steps of: (a) identifying a subject in need of markedly disturbs the fluency of speech. Typically, the treatment; and (b) administering to the Subject a therapeu disorder includes repeated articulatory movements (e.g., tically effective amount of a composition comprising a t-t-t-talk) and/or fixed articulatory movements (e.g., mmm D1/D5 receptor antagonist, a D1/D5 receptor partial agonist, mine). Verbal interjections (e.g., “um' or “like') are com or a mixture thereof. The Subject can be a human and can be mon. Verbal signs can be accompanied by nonverbal signs, of any age (e.g., a young child of about 2-4 years old; an including facial grimaces, excessive eye blinking, muscle older child or young adult of about 17, 18, or 21 years old, tension, odd movements of the head, and struggling to or an older person who is at least 17, 18, or 21 years old). speak. These behaviors may be learned approaches to mini It is believed that about 1% of the global population of all mize the severity of a stutter. People who stutter often ages, ethnicities, and cultures Stutter, and patients of any age experience emotional distress, and anxiety can cause them to or ethnicity can be treated as described herein. avoid educational and social situations that they would 0008. The subject in need of treatment may have been otherwise enjoy and benefit from. diagnosed as having developmental, neurogenic, or psycho 0004. The neurophysiological basis of stuttering is genic Stuttering (the latter two are also referred to as thought to share some similarities with other movement acquired Stuttering). Developmental Stuttering usually disorders. Specifically, Stuttering may arise due to abnormal occurs at the beginning of words and non-verbal, secondary signaling in one or more of the circuits between the cortex, behaviors may be more pronounced than they are with striatum, globus pallidus, and thalamus (the cortical-striatal acquired Stuttering. Developmental Stuttering manifests dur pallidal-thalamo or CSPT circuit). Circuit models have ing the period of extensive speech and language develop implied that excess dopamine activation increases unwanted ment. Its onset is usually gradual, occurring between about movements of the muscles controlling speech (at D1 recep 3 and 8 years of age, and spontaneous remission can occur tors) and, conversely, that dopamine blockade (at D2 recep within about four years. In a minority of children, there is no tors) promotes unwanted movements. Known D2 antago spontaneous resolution or relief from speech therapy, leav nists like clozapine, olanzapine, asenapine, and risperidone ing them with persistent developmental Stuttering that have all been reported to induce stuttering (Grover et al., requires further intervention. 2012: Bar et al., 2004: Yaday, 2010; Maguire et al., 2011) 0009. In other embodiments, the subject in need of treat and D2-preferring dopamine agonists such as methylpheni ment has been diagnosed as having neurogenic Stuttering, date have been reported to relieve stuttering (Devroey et al., which is triggered by brain damage. More specifically, 2012). neurogenic Stuttering can be caused by a traumatic head 0005 We are unaware of any treatments approved by any and/or brain injury, a stroke or any type of vascular blockage recognized government regulatory authority for the treat or bleeding within the brain (e.g., an intracerebral hemor ment of stuttering. Most patients are treated with behavioral rhage), a neurodegenerative disease such as Alzheimer's techniques (see Blomgren, Psychol. Res. Behay. Manage disease or Creutzfeldt-Jacob disease, or any encephalopathy. ment, 6:9-19, 2013). When used in severely afflicted Psychogenic Stuttering is characterized by the rapid repeti patients, pharmacotherapy typically involves drugs for the tion of the initial sounds of a word, and it is seen in adults treatment of anxiety (see, e.g., Maguire et al., J. Clin. with a history of psychological illness or emotional trauma. Psychopharmacol. 30:48-56, 2010). This is based on the Accordingly, patients amenable to treatment include those observation that stress exacerbates Stuttering and the who develop a Stutter secondary to brain damage or in the assumption that reducing stress will relieve some symptoms. context of a psychological illness or emotional trauma. US 2016/0271141 A1 Sep. 22, 2016 0010. The D1/D5 receptor antagonist can be ecopipam or Stuttering arises from a brain injury) that are designed to a pharmaceutically acceptable salt, Solvate, hydrate, prod reduce the frequency or severity of the verbal and/or non rug, structural analog, metabolite, or polymorph thereof. In Verbal signs of Stuttering or to increase a patient’s ability to the course of this application, we may provide lists such as cope. The methods can also be carried out following or in this one. It is to be understood that only one item may be connection with genetic testing. Several genetic studies have selected; that a combination of items may be selected; and that one or more of the listed items may be purposefully identified linkage to numerous loci across the genome, excluded. For example, a formulation useful as described spanning about a dozen chromosomes. Several genes and herein can include ecopipam; a pharmaceutically acceptable certain specific mutations are reviewed by Kraft and Yairi salt of ecopipam; or a mixture of ecopipam and a pharma (Folia Phoniatrica et Logopaedica, 64:34-47, 2012; see also ceutically acceptable salt thereof. Further, any of these Newbury and Monaco, Neuron, 68:309-320, 2010). The alternatives can explicitly exclude any other listed item. For accompanying therapy or process may also include imaging. example, a formulation useful as described herein can Neuroimaging and studies involving certain dopamine include ecopipam but exclude a structural analog thereof. receptor antagonists Support the theory of a hyperdopamin 0011. The compound administered (e.g., a D1/D5 recep ergic origin of Stuttering. A number of clinical trials for tor antagonist) can be formulated for oral delivery (e.g., Stuttering have been carried out for various drugs and have formulated in a unit dosage form of about 0.01 mg/kg to shown variable degrees of efficacy (reviewed by Bothe et al., about 500 mg/kg (e.g., about 0.01 mg/kg to about 50 mg/kg: American Journal of Speech-Language Pathology, 15:321 about 0.01 mg/kg to about 5 mg/kg, or about 0.1 mg/kg to 341, 2005).
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