US 2005O256029A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0256029 A1 Murphy et al. (43) Pub. Date: Nov. 17, 2005 (54) METHODS AND COMPOSITIONS FOR Publication Classification ALLEVIATING STUTTERING (51) Int. Cl." ....................... A61K 38/17; A61K 31/573; (75) Inventors: John J. Murphy, Manhattan Beach, A61K 31/5513; A61K 31/473; CA (US); Kay Jorgenson D’Orlando, A61K 31/4745; A61K 31/515 Wayland, MA (US) (52) U.S. Cl. .............................. 514/2; 514/179; 514/270; 514/221; 514/300; 514/290 Correspondence Address: KATTEN MUCHIN ROSENMAN LLP (57) ABSTRACT 525 WEST MONROE STREET Methods of treating Stuttering include treating people with CHICAGO, IL 60661-3693 (US) gamma-aminobutyric acid (GABA) receptor modulators, including cyclopyrrolones. A Second active agent may be (73) Assignee: Indevus Pharmaceuticals, Inc., Lexing used with GABA receptor modulators. Active enantiomers, ton, MA active metabolites, and pharmaceutically acceptable Salts of gamma-aminobutyric acid receptor modulators, including (21) Appl. No.: 11/046,706 cyclopyrrolones, are acceptable components of the compo Filed: Feb. 1, 2005 Sitions. The cyclopyrrolone class of modulators includes (22) pagoclone, Suriclone, Zopiclone, 2-(7-chloro-2-naphthyri Related U.S. Application Data din-1,8-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one, 2-(7- chloro-2-naphthyridin-18-yl)isoindolin-1-yl-4-acetami (63) Continuation of application No. 09/628,803, filed on dobutyrate, and 2-(7-chloro-1,8-naphthyridin-2yl)-3-(5- Jul. 28, 2000, now Pat. No. 6,855,721. methyl-5-hydroxy-2-oxohexyl)-1-isoindolinone. US 2005/0256029 A1 Nov. 17, 2005 METHODS AND COMPOSITIONS FOR 0006 Notably Wells, P. G. et al. Br J Psychiatry 1971, ALLEVIATING STUTTERING 119, 603, reported a placebo-controlled, double-blind study. Wells et al., randomized patients into treatment groups, 1. FIELD OF THE INVENTION included objective measures of Speech, and found a signifi cant improvement over an eight-week course. Objective 0001. The present invention relates generally to methods criteria in Such studies include the length of time to read a for treating Stuttering. The invention also relates to pharma Standard passage, the number of Syllabic repetitions in the ceutical compositions for treating Stuttering, comprising process of conveying Specific information, the time to gamma-aminobutyric acid modulators and pharmaceutically explain a Solution to a puzzle, and the like. Subsequent acceptable Salts thereof, including the cyclopyrrolones, Studies Support a significant improvement in the accessory notably pagoclone (+)2-(7-chloro-1,8-naphthyridine-2-yl)- Symptoms of Stuttering, including rapid blinking and jerking 3-(5-methyl-2-oxo-hexyl)-1-isoindolinone, alone or in movements of the upper body, but patient compliance is low combination with one or more pharmaceutically active because of Side-effects including dizzineSS and dysphoric agents, and a pharmaceutically acceptable carrier. "medicine-head’ symptoms. More Significant and disturbing are the long-term detrimental effects haloperidol and other 2. BACKGROUND OF THE INVENTION neuroleptics have on Voluntary muscle function, known as 0002 2.1. Developmental and Neurogenic Stuttering. tardive dyskinesia. 0.003 Stuttering is a poorly understood condition marked 0007 2.2 The GABA Neuronal Pathway. by frequent repetitions or prolongations of Sounds, and an 0008 One of the main neurotransmitters involved in impaired fluency of Speech. Accessory features of Stuttering, inhibitory neuronal pathways is gamma-aminobutyric acid possibly resulting from the attempts of the Stutterer to or GABA. GABA appears to function mainly at two types of control the Stuttering, include blocks in the flow of Speech receptors, termed GABA and GABA receptors, that have Sounds, Swallowing, grimacing, tremors of the jaw and different structures. The GABAA receptor is a GABA-gated tongue, coughing, rapid eye blinking, and jerking move chloride ion channel and the GABA receptor is a G-protein ments of the arm or upper trunk. (Brady, J. Am J Psychiatry, coupled regulator of potassium conductance. GABA recep 1991, 148, 1309). One form, developmental stuttering, often tors can be modulated by Several classes of pharmacologic appears in early human childhood or adolescence, and agents, notably the benzodiazepines, the barbiturates, con affects predominantly males. An estimated three million Vulsants, and neurosteroids of the class epiallopregnanolone Americans are affected and the condition is not dependent on or epalons. These classes of agents appear to act at different, language type or cultural background. A leSS frequent type discrete sites on the GABAA receptor. Thus, the diversity of is neurogenic Stuttering, often a result of head trauma or effects expressed by these agents ranges from the tranquil Stroke. Subtle differences between neurogenic and develop izing effects of benzodiazepines, and the Sedative effects of mental dysfluency may be observed, for example in the barbiturates to the convulsant effects of t-butyl-bicyclophos repetitive reading test, where Sufferers of developmental phorothionate (TBPS), which may act on GABAA receptors Stuttering often improve by the tenth reading of a passage, asSociated with clathrin-coated vesicles. The cyclopyrrolo but Sufferers of neurogenic Stuttering do not. A third type is nes have demonstrated high affinity for the benzodiazepine drug-induced Stuttering, an increasingly frequent problem. binding site on the GABAA receptor. Some cyclopyrrolones, 0004. In the past, stutterers have been treated by a wide e.g., pagoclone, have a pharmacological profile consistent variety of methods devised by some of the best minds of the with that of a partial agonist at this site. Partial agonists can time. Both Hippocrates and Hieronymus Merculialis recom be efficacious in producing Some effects, e.g., anxiolysis, in mended oral or head Surgeries or mutilations. In this century, common with full agonists, but may be less effective in psychiatric treatments have been tried ranging from operant producing others, e.g., Sedation. Antagonists, or “blockers,” reinforcement to psychotherapy for presumed unconscious on the other hand, counteract the action of endogenous conflicts. However, those who stutter are remarkably well GABA and exogenous agonists. Inverse agonists decrease adjusted, and are Similar to those who do not Stutter in the inherent or constitutive. Stimulation by a receptor in the personality traits. Current methods include Speech training absence of an agonist. Modulator is a term that includes and pharmaceutical intervention. The improvement for agonist, partial agonist, inverse agonist, antagonist, neu patients, unfortunately, has been limited. rotransmitter, reuptake inhibitor, and degradation inhibitor. Antagonists are often relatively Specific to a particular class 0005 The spectrum of experimental pharmaceutical of agonists. For example, flumazenil, a benzodiazepine interventions has been broad. At times, carbon dioxide inhalation, Stimulants (notably methamphetamine), Seda antagonist, blocks the function of benzodiazepines including tives (in particular, phenobarbital combined with belladonna flunitrazepam, diazepam, pinazepam, prazepam, halazepam, and ergotamine), an early antihistamine (hydroxy Zinc), bro camazepam, and flurazepam. mides, thiamine Supplements, an antihypertensive (reser 0009 GABAA receptor modulators, especially agonists pine), the tranquilizer meprobamate, anxiolytics (in particu and partial agonists, are also known to act as antiphobics, lar, benzodiazepines), neuroleptics (including thioridazine, myorelaxants, anti-epileptics, and by other means. GABAA chlorpromazine and trifluoperazine), Verapamil, beta-adren receptor modulators act as myorelaxants by decreasing ergic blockers (including propranolol, betaxolol, and Oxpre muscle Stiffness, decreasing tonus, and reducing Voluntary nolol), an anticonvulsant (carbamazepine), and cholinergic muscle contraction in Spasticity. Also Some GABA modu agents (neostigmine and bethanecol) have been tried for lators have hypnotic, Sleep-inducing, amnestic, Sedative, Stuttering, but all with unsustainable Success. Haloperidol and/or anti-convulsant effects. Antagonists of GABAA has been particularly well Studied as an agent for the receptor function tend to block these effects and may even attenuation of Stuttering. be anxiogenic or proconvulsant in Some individuals. US 2005/0256029 A1 Nov. 17, 2005 0.010 Many of the GABA agonists, in particular the methyl-1-piperazinecarboxylic acid 6-(5-chloro-2-pyridi benzodiazepines and the cyclopyrrolones, act to reduce nyl)-6,7-dihydro-7-oxo-5H-pyrrolo-3.4pyrazin-5-yl ester), anxiety and induce a Sense of calm. In consequence, these and the compound of U.S. Pat. No. 5,676,831. Use of active agents are termed anxiolytics. It has long been thought that metabolites, active enantiomers, active racemic mixtures, or anxiety is a component of Stuttering, although the cellular pharmaceutically acceptable Salts of cyclopyrrolones, as an bases for anxiety and Stuttering are not at all clear. In anti-Stuttering medication is contemplated. contrast, however, the results of placebo-controlled Studies 0018. In a yet further object of the invention, pagoclone, of benzodiazepines on Stuttering have been inconsistent and its active metabolite, its active enantiomer, an active racemic disappointing (Brady, Supra). mixture comprising pagoclone, or pharmaceutically accept 0.011) 2.3 Drug-Induced Stuttering.