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. able Salts thereof, are contemplated as an anti-Stuttering 0012. A different approach, that of evaluating drug-in medication. duced Stuttering, has led to Some useful observations, but no 0019. The present invention is useful for treating, allevi cure. Part of the confusion is that many drugs induce ating or preventing Stuttering. In an embodiment of the Stuttering. Several workers have reported that phenothiaz invention, the Stuttering can be characterized as being devel ines induce Stuttering, whether administered alone or with opmental, neurogenic or drug-induced Stuttering. Likewise, other agents. This drug-induced Stuttering was accompanied Stuttering is understood to include common Stuttering, motor by akathisia, or a “cant sit still' syndrome. Rentschler, G. tic, clonic Stuttering, dysfluency, speech blockage, impaired J. et al., J. Fluency Disord 1984, 9, 265 and Elliot, R.I. et al., phonation, dysarthria, Tourette's Syndrome, developmental J Clin Psychopharmacol 1985, 5, 159, report stuttering in Stuttering, neurogenic Stuttering, drug-induced Stuttering, response to benzodiazepines. Alprazolam, a potent anxi logospasm, and the like. There can be different organic, olytic, can induce Stuttering (Elliot, Supra). genetic, or developmental origins of the Stuttering. 0013 Most of the other cases of drug-induced stuttering 0020. In addition, the present invention also contemplates are related to inhibition of Serotonin uptake, usually with the a pharmaceutical composition Suitable for alleviating Stut drugs sertraline or fluoxetine (Brady, J. P. J. Clin Psychop tering in a perSon afflicted with Stuttering which comprises harmacol 1988, 18, 50), which are also considered to be (i) at least one GABAA receptor modulator, active enanti anxiolytics. The induced Stuttering was frequently accom omer, active metabolite, or pharmaceutically acceptable Salt thereof; (ii) at least a Second pharmaceutically active agent; panied by akathisia in these cases as well. and (iii) a pharmaceutically acceptable carrier. 0.014 Thus, the state of the art underscores the prevailing and unfilled need for an effective pharmacologic treatment 0021. In a more particular aspect, the invention relates to of Stuttering. Indeed, the long-standing effort to cure or a pharmaceutical composition comprising a GABAA modu relieve Stuttering has engaged many clinicians over decades, lator, including but not limited to pagoclone, Suriclone(4- centuries, and even millennia. At least two conclusions may methyl-1-piperazinecarboxylic acid 6-(7-chloro-1,8-naph be reached from the wide range of pharmacologic treatments thyridin-2-yl)-2,3,6,7-tetrahydro-7-oxo-5H-1,4-dithiino 2,3- attempted for Stuttering. The first is that no clear understand cpyrrol-5-yl ester); Zopiclone(4-methyl-1- ing of the underlying basis for Stuttering exists. The Study of piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7- Stuttering is particularly intractable because there exist no dihydro-7-oxo-5H-pyrrolo-3.4pyrazin-5-yl ester); 2-(7- animal models and the evaluation of improvement in Stut chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-5-hydroxy-2- tering is fraught with Subjective criteria. The Second is that oxohexyl)-1-isoindolinone, their active enantiomers, their no known agent, or combination of agents, is effective in metabolites, or pharmaceutically acceptable Salts thereof, treating this widespread difficulty. alone-or in combination with an agent Selected from the group consisting of analgesics, abortifacients, ACE inhibi tors, alpha-adrenergic agonists, alpha-adrenergic antago 3. SUMMARY OF THE INVENTION nists, beta-adrenergic agonists, beta-adrenergic antagonists, 0.015. In a general aspect, the present invention relates to adrenocortical Steroids, adrenocortical SuppreSSants, adreno a method for alleviating Stuttering, which comprises admin corticotropic hormone, alcohol deterrents, aldose reductase istering a preparation including an effective amount of one inhibitors, aldosterone antagonists, 5'-alpha reductase or more GABA receptor modulators. inhibitors, analgesics, androgens, anesthetics, antacids, 0016. It is an object of the invention to provide a method anthelmintics, antiallergics, antialopecia agents, antiame for alleviating Stuttering, which comprises administering a bics, antiandrogens, antianginals, antiarrhythmics, antiarthe riosclerotics, antiarthritics, antiasthmatics, antibiotics, anti therapeutically effective dose of a preparation Selected from cholelithogenics, anticholesterimics, anticholinergics, the class of benzodiazepines. Use of active metabolites, anticoagulants, anticonvulsants, antidepressants, antidiabet active enantiomers, active racemic mixtures, or pharmaceu ics, antidiarrheals, antidiuretics, antidyskinetics, antieczem tically acceptable Salts of benzodiazepines, as an anti-Stut atics, antiemetics, antiepileptics, antiestrogens, antifibrotics, tering medication is contemplated. antiflatulents, antifungals, antiglaucoma agents, antihista 0.017. It is another object of the invention to provide a minics, antihypertensives, antihypotensives, anti-inflamma method for alleviating Stuttering, which comprises admin tories, antimalarials, antimanics, antimigraines, antineoplas istering a therapeutically effective dose of a preparation tics, antiosteoporotics, antiprotozoals, antipruritics, Selected from the class of cyclopyrrolones. The class of antipsychotics, antivirals, other anxiolytics, bronchodilators, cyclopyrrolones includes, but is in no way limited to, vasodilators, contraceptives, decongestants, diuretics, anti pagoclone, Suriclone(4-methyl-1-piperazinecarboxylic acid migraines, immunosuppreSSants, inotropic agents, laxatives, 6-(7-chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-7- muscle relaxants, Supplements, prophylactics of urinary oxo-5H-1,4-dithiino 2,3-cpyrrol-5-yl ester), Zopiclone(4- tract infections, and Vitamins. US 2005/0256029 A1 Nov. 17, 2005

0022. A further object of the invention relates to admin pregnanolone, pregnenolone, progesterone, propofol, pro istration of independent pharmaceutical preparations to the pylbicyphat, quazepam, 2-(7-chloro-2-naphthyridin-18-yl)- Same patient at the same time or different times, preferably 3-(5-methyl-2-oxohexyl)isoindolin-1-one, also known as at about the same time, and by the same or different modes RP59037; 2-(7-chloro-2-naphthyridin-18-yl)isoindolin-1- of administration, where one pharmaceutical preparation yl-4-acetamidobutyrate also known as RP60503, 2-(7- comprises a GABAA receptor modulator and the Second chloro-1,8-naphthyridin-2yl)-3-(5-methyl-5-hydroxy-2- pharmaceutical preparation comprises a different agent. oxohexyl)-1-isoindolinone also known as RPR101769, Secobarbital, Suriclone, tenazepam, tetrahydrodeoxycorti 4. DETAILED DESCRIPTION OF THE costerone, tetramethylene Sulfotetramide, thiopental, triaz INVENTION olam, Zopiclone, and pharmaceutically acceptable Salts 0023 The present invention contemplates a method of thereof. Active enantiomers, active metabolites and active alleviating Stuttering in a perSon, comprising administering racemates of these agents, if they exist, are equally Suitable. an effective Stuttering alleviating amount of at least one 0028. The present invention provides a new method of GABA receptor modulator, an enantiomer of the modulator, treatment of Stuttering using pharmaceutical compounds that an active metabolite of the modulator, or a pharmaceutically preferentially modulate GABAA receptors In particular, the acceptable Salt of the modulator. One embodiment is a useful compounds of the invention are cyclopyrrolones GABA receptor modulator effective at the receptor Subtype according to Formula I, metabolites thereof, enantiomers A. thereof, racemates thereof, and Salts including acid addition Salts thereof, alone or in conjunction with one or more other 0024. A method of the present invention includes the therapeutic agents: treatment of the developmental Stuttering and dysfluency that manifests itself, commonly, in adolescence or child hood. Another method of the present invention includes the treatment of Stuttering and dysfluency that can occur after (I) trauma to head and body tissues, e.g., those resulting from Surgery, injuries, etc. Hence, the pharmaceutical treatment according to the present invention can be administered prior to or after Surgery. The present invention contemplates the treatment of drug-induced Stuttering as yet another embodi C-2) ment. 0.025) Any mode of administration may be used. It is preferred, however, that the mode of administration is o Selected from parenteral, oral, vaginal, rectal, nasal, buccal, intravenous, intramuscular, Subcutaneous, intrathecal, epi dural, intracerebroVentricular, transdermal, or combinations 0029 wherein: thereof. The GABAA receptor modulator, enantiomer of the 0030 (a) R and R are the same or different steri modulator, active metabolite of the modulator, or pharma cally compatible Substituents which are Selected ceutically acceptable Salt of the modulator, can act in the from the group consisting of hydrogen; alkyl having central nervous System, including Spinal cord, or in the 1 to 8 carbon atoms, alkyl having 1 to 8 carbon peripheral nervous System, the neuro-muscular System or atoms, and having at least one of nitrogen, OXygen, elsewhere. These agents can have transient action, Sustained Sulfur, or phosphorus, aryl having 1 to 8 carbon action or persistent action. atoms, and aryl having 1 to 8 carbon atoms and 0026. The means of administration will be evident to one having at least one nitrogen, oxygen, Sulfur, or skilled in the art, who will know, for example, that Some phosphorus, agents must be brain permeant, either in and of themselves, 0031 (b) R is selected from the group of substitu or facilitated by a Suitable device or carrier, whereas others ents consisting of alkyl, alkenyl, alkynyl, alkoxy, should not cross the blood brain barrier. alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, 0027. A wide variety of agents active at GABAA recep alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfi tors are Suitable for use in the present invention, including nyl, alkylthio, alkanoylamino, alkenoylamino, cyclopyrrolones, benzodiazepines, general anesthetics, bar alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbony biturates, and, neurosteroids, alone or in combination. Suit lamino, alkoxycarbonylaminoalkyl, aryl, aryl, able components are: allopregnanolone, alphaXalone, alpro cycloalkyl having 3 to 6 ring members, cycloalkenyl Zolam, amobarbital, aprobarbital, avermectin B, itbaclofen, having 4 to 6 ring members, cycloalkylalkyl having bicuculline, butabarbital, butalbital, camazepam, cloflubi 3 to 6 ring members, cycloalkenylalkyl having 4 to cyne, chlordiazepoxide, clorazepam, chloraZepate, diaz 6 ring members, with the proviso that each of the epam, diazepam binding inhibitory protein, diazepam bind foregoing R. Substituents has up to 8 carbon atoms, ing inhibitory protein fragment, dihydroepiandrosterone, trifluoromethyl, nitro, amino, hydroxyl, halogen, epiallopregnanolone, estazolam, etbicuphat, etbicythionat, aminocarbonyl, cyano, cyanoalkyl having from 2 to etomidate, flucybene, flunitrazeparn, flurazepam, 4 carbon atoms, aminocarbonylalkyl having 2 to 4 halazepam, D-B-hydrastine, isobicyphat, lorazepam, mebi carbon atoms, aryl, alkaryl, piperazinyl, and methyl cyphat, mephobarbital, methohexital, midazolam, piperazinyl, oxazepam, pagoclone, pentobarbitone, pentobarbital, phe 0032 (c) X and X- are the same or different steri nobarbital, picrotoxinin, picrotin, pinazepam, prazepam, cally compatible Substituents which are Selected US 2005/0256029 A1 Nov. 17, 2005

from the group consisting of hydrogen, alkyl, alk addition Salts which do not meet the foregoing criteria for enyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkoxy pharmaceutical acceptability, for instance as to toxicity, are alkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, Sometimes useful as intermediates for isolation and purifi alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoy cation of the present Substances or for other chemical lamino, alkenoylamino, alkoxycarbonyl, alkenoxy Synthetic purposes Such as Separation of optical isomers. carbonyl, alkoxycarbonylamino, alkoxycarbony Such Salts are also part of the invention. laminoalkyl, aryl, cycloalkyl having 3 to 6 ring 0036) The acid addition salts are made by reaction of a members, cycloalkenyl having 4 to 6 ring members, base of the structural formula I with the acid, preferably by cycloalkylalkyl having 3 to 6 ring members, contact in Solution. They also are made by metathesis or cycloalkenylalkyl having 4 to 6 ring members, with treatment with an anion exchange resin whereby the anion of the additional proviso that each of the foregoing X one Salt of the Substance is replaced by another anion under and X. Substituents has up to 8 carbon atoms, trif conditions which allows for Separation of the undesired luoromethyl, nitro, amino, hydroxyl, halogen, ami Species Such as by precipitation from Solution or extraction nocarbonyl, cyano, cyanoalkyl having from 2 to 4 into a Solvent or elution from or retention on an anion carbon atoms, aminocarbonylalkyl having 2 to 4 eXchange resin. Pharmaceutically acceptable acids for the carbon atoms, and purposes of Salt formation include hydrochloric, hydrobro 0033 (d) X is selected from the group consisting of: a mic, hydroiodic, citric, acetic, benzoic, phosphoric, nitric, methylene;-C(HR)- where R is selected from the group mucic, isethionic, methaneSulfonic, p-toluenesulfonic, glu of Substituents consisting of alkyl, alkenyl, alkynyl, alkoxy, cosaccharic, palmitic, heptanoic, oxalic, cyclamic, Succinic, alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, malic, fumaric, mandelic, malonic, and others. alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alky 0037. The compounds of the present invention shown by lthio, alkanoylamino, alkenoylamino, alkoxycarbonyl, alk the Structural formula I contain an asymmetric carbon atom enoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylami in the cyclopyrrolone ring and occur as optically active noalkyl, aryl, cycloalkyl having 3 to 6 ring members, isomers as well as racemic mixtures thereof. The present cycloalkenyl having 4 to 6 ring members, cycloalkylalkyl invention is intended to include each of the optically pure, having 3 to 6 ring members, cycloalkenylalkyl having 4 to optically active and racemic forms. Some of the Substances 6 ring members, with the additional proviso that each of the of the present invention contain an asymmetric carbon atom foregoing R. Substituents has up to 8 carbon atoms, trifluo in the X, X, R, R2, or R. Substituents in formula I, and romethyl, nitro, amino, hydroxyl, halogen, aminocarbonyl, diastereoisomeric pairs of racemates exist. These forms are cyano, cyanoalkyl having from 2 to 4 carbon atoms, and also contemplated and included in the methods of the aminocarbonylalkyl having 2 to 4 carbon atoms, amino; present invention. -N(R)- where R is selected from the group of substitu ents consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, 0038 Resolution of racemic mixtures to provide the alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, alkanoyloxy, alk optically active isomers of the foregoing compounds is enoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoy carried out, for example, by forming a Salt with an optically lamino, alkenoylamino, alkoxycarbonyl, alkenoxycarbonyl, active acid many of which are known to those skilled in the alkoxycarbonylamino, alkoxycarbonylaminoalkyl, art Such as optically active tartaric, mandelic, cholic, O,O- cycloalkyl having 3 to 6 ring members, cycloalkenyl having di-p-toluoyl tartaric, and O,O-dibenzoyl tartaric acids, or 4 to 6 ring members, cycloalkylalkyl having 3 to 6 ring other acids conventionally employed for this purpose. Sepa members, cycloalkenylalkyl having 4 to 6 ring members, ration of optical isomers can be accomplished as disclosed with the additional proviso that each of the foregoing Rs in U.S. Pat. No. 4,960,779 which is incorporated herein by Substituents has up to 8 carbon atoms, trifluoromethyl, nitro, reference. amino, hydroxyl, halogen, aminocarbonyl, cyano, 0039 For the preparation of pharmaceutical composi cyanoalkyl having from 2 to 4 carbon atoms, and aminocar tions containing the compounds of Formula I in the form of bonylalkyl having 2 to 4 carbon atoms, Sulfur, phosphorus, dosage units for oral administration, the compound is mixed and oxygen group; pharmaceutically acceptable Salts with a Solid, pulverulent carrier Such as lactose, Sucrose, thereof, enantiomers thereof, or metabolites thereof. Sorbitol, mannitol, potato Starch, corn Starch, amylopectin, 0034) The R and R. Substituents can be on positions 3, cellulose derivatives, or gelatin, as well as with glidents Such 4, 5, or 6 of the ring. as magnesium Stearate, calcium Stearate, polyethylene gly 0035. The invention includes compounds having the col waxes or the like and pressed into tablets. The tablets are structural formula I and the acid addition salts thereof. For used uncoated or coated by known techniques to delay medical use, the pharmaceutically acceptable acid addition disintegration and absorption in the gastrointestinal tract and Salts are preferred. The pharmaceutically acceptable acid thereby provide a Sustained action over a longer period. addition Salts are those Salts in which the anion does not When coated tablets are desired, the above prepared core is contribute Significantly to the toxicity or pharmacological coated with a concentrated Solution of Sugar, which Solution activity of the Salt, and as Such, they are the pharmacological may contain e.g., gum arabic, gelatin, talc, titanium dioxide equivalents of the bases having the foregoing structural or the like. Furthermore, the tablets are coated with a lacquer formulas. In Some instances, the Salts have physical prop dissolved in an easily Volatile organic Solvent or mixture of erties which make them more desirable for pharmaceutical Solvents and if desired, dye is added to this coating. formulation purposes Such as Solubility, lack of hygroscop 0040. In the preparation of soft gelatin capsules consist icity, compressibility with respect to tablet formation and ing of gelatin and e.g., glycerine and the like, the active compatibility with other ingredients with which the Sub ingredient is mixed with a vegetable oil and encapsulated in stances may be used for pharmaceutical purposes. Acid conventional manner. Hard gelatin capsules may contain US 2005/0256029 A1 Nov. 17, 2005 granules of the active ingredient in combination with a Solid, lose Sodium, carrageenan, powdered cellulose, guar gum, pulverulent carrier Such as lactose, Saccharose, Sorbitol, cholesterol, gelatin, gum agar, gum arabic, gum karaya, gum mannitol, Starch (Such as e.g. potato Starch, corn Starch, or ghatti, locust bean gum, Octoxynol-9, oleyl alcohol, pectin, amylopectin), cellulose derivatives or gelatin. poly(acrylic acid) and its homologs, polyethylene glycol, polyvinyl alcohol, polyacrylamide, Sodium lauryl Sulfate, 0041 Dose units for rectal administration may be pre poly(ethylene oxide), polyvinylpyrrolidone, glycol pared in the form of Suppositories containing the compound monoStearate, propylene glycol monoStearate, Xanthan gum, in a mixture with a neutral fat base, or in the form of a tragacanth, Sorbitan esters, Stearyl alcohol, Starch and its gelatin-rectal capsule with a mixture of vegetable oil or modifications. Suitable ranges vary from about 1% to about paraffin oil. 50% by weight of the total composition. 0.042 Liquid preparations suitable for oral administration 0049 Preferred GABA receptor modulators are cyclo are Suspensions, Syrups and elixirs containing from about pyrrolones, including, but not limited to, pagoclone; Zopi 0.2% by weight to about 20% by weight of the active clone; Suriclone; 2-(7-chloro-2-naphthyridin-18-yl)-3-(5- ingredient. methyl-2-oxohexyl)isoindolin-1-one, 2-(7-chloro-2- 0.043 A Suitable injectible composition is comprised of naphthyridin-1,8-yl)isoindolin-1-yl-4-acetamidobutyrate, an aqueous Solution of a water Soluble pharmaceutically 2-(7-chloro-1,8-naphthyridin-2yl)-3-(5-methyl-5-hydroxy acceptable acid addition Salt adjusted to physiologically 2-oxohexyl)-1-isoindolinone, active metabolites thereof, acceptable pH. enantiomers thereof, and pharmaceutically acceptable Salts 0044) The present invention relates to a pharmaceutical thereof. The most preferred GABAA receptor modulator is composition for alleviating Stuttering, which comprises: (a) pagoclone, as shown by formula II, where the asterisk an effective amount of a first active ingredient, which indicates the chiral atom, and pharmaceutically acceptable comprises at least one GABAA receptor modulator, includ salts thereof. ing, but not limited to the cyclopyrrolone class of agents, enantiomers, metabolites, and pharmaceutically acceptable Salts thereof, optionally, (b) an effective amount of a second (II) active agent; and optionally (c) a pharmaceutically accept able carrier. 004.5 The terms “effective amount;"therapeutically effective amount,” or “pharmaceutically effective amount” of a compound in unit dosage form of the composition depends upon a number of factors. Included among these factorS is the quantity of the other ingredients when used. An effective amount of the active ingredient ranges from about 1% to about 100% by weight based on the total weight of the composition but, in any event, is Sufficient to observe the anticipated benefit. 0.046 By “pharmaceutically acceptable carrier' is meant 0050 GABAA modulators suitable for use in the present Solid or liquid filler, diluent, or encapsulating Substance, invention can exist as Salts. In particular, the compounds of which may be safely used in Systemic or topical adminis the invention can form acid addition Salts of pharmaceuti tration. Depending on the particular route of administration, cally acceptable inorganic or organic acids. Examples of a variety of pharmaceutically acceptable carriers well known Suitable inorganic acids include, but are not limited to, in the art may be used, ineluding Solid or liquid fillers, hydrochloric, hydrobromic, Sulfuric, phosphoric, or nitric diluents, hydrotropies, Surface active agents, and encapsu acid. Examples of Suitable organic acids include, but are not lating Substances. The amount of a carrier employed in limited to, aliphatic or aromatic carboxylic or Sulfonic acids, conjunction with the GABAA receptor modulator is Suffi for example, acetic, propionic, Succinic, glycolic, lactic, cient to0 provide practical quantity of material per unit dose fumaric, tartaric, tannic, gluconic, citric, ascorbic, maleic, of GABAA receptor modulator. Pharmaceutically acceptable pyruvic, palmoic, oxalic, dioxalic, nicotinic, methane carriers for Systemic administration, which may be incor Sulfonic, ethaneSulfonic, hydroxyethaneSulfonic, benzene porated in the composition of the invention, include Sugar, Sulfonic, p-toluenesulfonic, or naphthaleneSulfonic acid. Starches, cellulose, vegetable oils, mineral oils, buffers, Preferred Salts include the hydrochloride, oxalate, fumarate, polyols, alginic acid and the like. Specific pharmaceutically citrate, tannate, or dioxalate Salts. acceptable carriers are described in U.S. Pat. No. 4,401,663; 0051) The GABA receptor modulators and salts thereof European Patent Application No. 089710; and European are discussed in detail in Remington's Pharmaceutical Sci Patent Application No. 0068592, which are incorporated ences (in Gennaro, A. et al., Ed., Mack Pub.Co., Easton, Pa. herein by reference. 18th ed. 1990, 1057-1071), the relevant portions of which 0047 Carriers for parenteral administration may include are incorporated herein by reference. propylene glycol, pyrrollidone, ethyl oleate, aqueous ethanol and combinations thereof. 0052 The pharmaceutical composition of the present invention can have a wide range of GABAA receptor modu 0.048 Still other representative carriers include acacia, lator dosage where a total dosage of about 0.01 to about agar, alginates, hydroxyalkylcellulose, hydroxypropyl meth 1000 mg is administered daily. More preferably, this dosage ylcellulose, carboxymethylcellulose, carboxymethylcellu is about 0.1 mg to about 10 mg. The frequency of doses can US 2005/0256029 A1 Nov. 17, 2005

vary from about one per day to about two per hour. The preservatives. Suitable dispersing or wetting agents and dosage can also be adjusted for body weight, from about Suspending agents are exemplified by those already men 0.001 mg/kg body weight/day to about 1.0 mg/kg body tioned above. Additional excipients include Sweetening, weight/day. flavoring and coloring agents. SyrupS and elixirs can be 0053. The administration of the GABAA receptor modu formulated with Sweetening agentS Such as glycerol, Sorbitol lator can be by intravenous, intramuscular, Subcutaneous, or Sucrose. Such formulations can contain demulcent, pre intrathecal, epidural, or intracerebroVentricular injection, or Servative, flavoring and coloring agents. parenterally, orally, vaginally, rectally, nasally, buccally, 0058. The stuttering alleviating agent can be adminis transdermally, and combinations thereof. tered in a Sustained release formulation. Methods for SuS tained release dosage forms are advantageously provided in 0.054 The administration of the stuttering alleviating or U.S. Pat. Nos. 4,788,055; 4,816,264; 4,828,836; 4,834,965; ameliorating Substance to the patient can be conducted in 4,834,985; 4,996,047; 5,071,646; and 5,133,974, which are conjunction with treatment for other ailments with the incorporated herein by reference. Second active agent, or other agents. Effective dosage levels can vary widely; actual amounts will depend on the agents 0059. The compositions of the invention have pharma used and the State and diagnosis of the patient being treated. cological advantages that render them useful for alleviating AS those skilled in the art would recognize, many factors Stuttering. In this application, at least one GABA receptor that modify the action of the Stuttering alleviating compo modulator and one or more Second active agent may be Sition and Second active agents herein will be taken into administered according to any convenient or effective account by the treating physician including, but not limited method for introducing foreign Substances into the blood to, Such factors as age, body weight, Sex, diet, and condition Stream of mammals, Such as by oral, rectal, nasal, buccal, of the patient, time of administration, rate and route of vaginal or parenteral routes. The effective dose levels may administration, psychiatric condition, other diseases, and So be administered on a regimen of about 1 to about 6 times a forth. Titration of dosage for individual patients, up to the day. The pharmaceutical formulation of the invention can be maximal dose permits attainment of functionally effective in dosage forms Such as pills, capsules, powders or granules doses. Optimal dosages for a given set of conditions can be for oral administration. The compounds can be conveniently ascertained by those skilled in the art using conventional administered in unit dosage form and can be prepared by any dosage determination tests in View of experimental data of the methods well known in the pharmaceutical art, for provided herein. example as described in Remington's Pharmaceutical Sci ences, supra, 1451-1459, 1504-1512, 1519-1570, and 1615 0.055 The stuttering alleviating substance of the instant 1693, which are incorporated herein by reference. invention will ordinarily be formulated with one or more pharmaceutically acceptable ingredients in accordance with 0060. The compounds of the invention can be formulated known and acceptable practice. The Stuttering alleviating into pharmaceutical compositions of an admixture with Substance can be formulated as a liquid, powder, aeroSol, pharmaceutically acceptable carriers. AS discussed above, elixir, injectable Solution, etc. Formulations for oral use can the compositions may be prepared for use by or in be provided as hard gelatin capsules wherein the Stuttering parenteral, that is, Subcutaneous, intramuscular, or intrave alleviating Substance is mixed with an inert Solid diluent nous, administration, particularly in the form of liquid Such as calcium carbonate, phosphate, or kaolin or, prefer Suspensions. Also, the composition can be prepared for oral ably, as Soft gelatin capsules wherein the Stuttering allevi administration, particularly in the form of tablets or cap ating Substance is mixed with an oleaginous medium, e.g., Sules, or intranasally, particularly in the form of powders, liquid paraffin or Soybean oil. nasal drops or aerosols. The composition can also be pre pared for use in vaginal or rectal administration. Formula 0056 Aqueous Suspensions can contain the Stuttering tions for parenteral administration may contain as common alleviating Substance in an admixture with pharmaceutically excipients, Sterile water, or Saline, polyalkylene glycols Such acceptable excipients Such as: Suspending agents, like car as polyethylene glycol, oils of vegetable origin, hydroge boxymethylcellulose, methylcellulose, hydroxypropylmeth nated naphthalenes and the like. Formulations for vaginal or ylcellulose, Sodium alginate, polyvinylpyrrollidone, gum rectal administration, e.g., Suppositories may contain as tragacanth, gum acacia; dispersing or Wetting agents. Such as excipients, for example, polyalkylene glycols Such as poly naturally occurring phosphatide, e.g., lecithin; or condensa ethylene glycol, petroleum jelly, cocoa butter and the like. tion products of an alkaline oxide with fatty acids, e.g., Formulations for inhalation administration may be Solid and polyoxyethylene Stearate or condensation products of eth contain excipients, for example, lactose, or may be acqueous ylene oxide with partial esters derived from fatty acids and or oily Solutions for administration in the form of nasal hexitol, e.g., polyoxyethylene Sorbitol monooleate, or con drops. For buccal administration, typical excipients include densation products of ethylene oxide with partial esters Sugars, calcium Stearate, magnesium Stearate, pregelatinated derived from fatty acids and hexitol anhydrides, e.g., poly Starch and the like. oxyethylene Sorbitan monooleate. Such aqueous Suspen 0061 For oral administration, a pharmaceutically accept Sions can also contain one or more preservatives, e.g., ethyl able composition can be formed by incorporation of any of or n-propyl-p-hydroxybenzoate, or one or more coloring the normally employed excipients, oral dose extenders or agents, flavoring agents and Sweetening agents. Such as carrierS Such as for example, pharmaceutical grades of Saccharose, Saccharin or Sodium or calcium cyclamate. mannitol, lactose, Starch, magnesium Stearate, Sodium sac 0057. In the preparation of aqueous suspensions, water is charin, talcum, cellulose, glucose, Sucrose, magnesium, car added to dispersible powders and granules to provide the bonate and the like. Such compositions can take the form of Stuttering alleviating Substance in an admixture with dis Solution, Suspension, tablets, pills, capsules, powders, Sus persing or Wetting agent, Suspending agent and one or more tained release formulations and the like. US 2005/0256029 A1 Nov. 17, 2005

0062) To produce tablets or dragée cores, the active a drug which works at the GABAA receptor, in the treatment Substances are combined with, e.g., Solid pulverulent carri of panic disorder, an anxiety disorder. She experiences a erS Such as lactose, Saccharose, Sorbitol, mannitol, Starches Significant reduction in her fairly Severe Stuttering problem Such as potato Starch, maize Starch, amylopectin, also lami while she is taking the pagoclone. The double-blind placebo naria powder or citrus pulp powder; cellulose derivatives or controlled trial conceals the drug type until the conclusion of gelatin, optionally with the addition of lubricants Such as the trial. During the trial the patient is taking 0.60 mg magnesium or calcium Stearate or polyethylene glycol of pagoclone/day (0.20 mg. t.i.d.). The patient had never before Suitable molecular weight to form tablets or dragée cores. experienced this Sort of an effect on her Stuttering and she The latter are coated, e.g., with concentrated Sugar Solutions had taken, in the past, other anti-anxiety medications for her which can also contain, e.g., gum arabic, talcum, titanium psychiatric condition, none of which had Such an effect on dioxide, or with lacquer dissolved in a mixture of Solvents. her Stuttering. During the trial, both She and the clinician Other Suitable oral dosage units are hard gelatin capsules as treating her in the clinical trial notice the reduction in her well as Soft, closed capsules from a gelatin Softener Such as Stuttering, which is documented at her week 2 Visit. Her glycerol. Stuttering returns to the pre-drug level within a day of 0.063 Examples of dosage units for rectal administration Stopping the pagoclone. She also experiences a reduction in are Suppositories that comprise a combination of at least one her anxiety and improvement in her psychiatric condition. GABAA receptor modulator, one or more Second active During the trial She also is taking ibuprofen and a prophy agents and a carrier Suppository foundation. Also Suitable lactic for urinary tract infections. are a gelatin rectal capsules, which contain a combination of 0069. 6.2 Large-Scale Trial Treatment, with Pagoclone, at least one of the above Substances with polyethylene glycol of Patients Suffering from Developmental Stuttering of Suitable molecular weight as carrier. 0070 Patients with stuttering problems are enrolled in a 0.064 Ampoules for parenteral, particularly intramuscu clinical trial examining the efficacy and Safety of pagoclone lar and also intravenous administration, preferably contain at in the treatment of developmental Stuttering. The open-label least one GABAA receptor modulator and one or more trial is administered by physicians. During the trial one Second active agents. If necessary, Suitable Stabilizing agents group of twenty patients is taking 0.60 mg pagoclone/day and/or buffer Substances are added to the ampule Solutions. (0.20 mg. t.i.d.), another group is taking 0.20 mg pagoclone/ 0065. These compounds can be encapsulated, tableted or day, and another group is taking a placebo. The patients have prepared in a emulsion or syrup for oral administration. never before experienced relief of Stuttering by a medica Pharmaceutically acceptable Solid or liquid carriers can be tion. During the trial, both the patients and the clinicians added to enhance or Stabilize the composition, or to facilitate treating them in the clinical trial monitor the Stuttering by a preparation of the composition. Liquid carriers include battery of objective tests, and document each case. Syrup, peanut oil, olive oil, Sesame oil, vegetable oil, mineral 0.071) 6.3 Large-Scale Treatment, wWith Selected oil, Soybean oil, cottonseed oil, glycerin, Saline, ethanol, and water. Solid carriers include Starch, lactose, calcium Sulfate GABA Modulators, of Patients Suffering from Stuttering dihydrate, terra alba, magnesium Stearate or Stearic acid, 0072 Patients with stuttering problems are enrolled in a talc, pectin, acacia, agar or gelatin. The carrier may also clinical trial examining the efficacy and Safety of Zopiclone, include a Sustained release material Such as glyceryl Suriclone, diazepam, propofol, alphaXalone, and pentobar monoStearate or glyceryl distearate, alone or with a wax. The bital, drugs which work at the GABAA receptor, in the amount of solid carrier varies but, preferably, will be treatment of developmental Stuttering. The patients are ran between about 20 mg to about 1 g per dosage unit. The domly assigned to one of eight groups. The double-blind pharmaceutical preparations are made following the con placebo-controlled trial conceals the drug type until the ventional techniques of pharmacy involving milling, mix conclusion of the trial. During the trial each group of ing, granulating, and compressing, when necessary, for patients is taking a therapeutically effective dose of one tablet forms, or milling, mixing and filling for hard gelatin agent or is taking the placebo. The patients have never capsule forms. When a liquid carrier is used, the preparation before experienced relief of Stuttering by a medication. is in the form of a Syrup, elixir, emulsion or an aqueous or During the trial, both the patients and the clinicians treating non-aqueous Suspension. Such a liquid formulation can be them in the clinical trial monitor the Stuttering by objective administered directly by mouth or filled into a soft gelatin evaluations of dysfluency, and document each case. capsule. 0073 6.4 Large-Scale Trial Treatment, with Pagoclone 5. EXAMPLES and a Second Active Agent, of Patients Suffering from Stuttering. 0.066 The following specific examples are provided to better assist the reader in the various aspects of practicing 0074 Patients with stuttering problems are enrolled in a the present invention. AS these Specific examples are merely clinical trial examining the efficacy and Safety of pagoclone illustrative, nothing in the following descriptions should be and a Second active agent in the treatment of developmental construed as limiting the invention in any way. Such limi Stuttering. The Second agents are ibuprofen, UTI Plus, tations are, of course, defined Solely by the accompanying propanolol, minoxidil, estrogen, citicoline, ergotamine, and claims. pregnanolone. Patients are randomly assigned to one of nine groups. The double-blind placebo-controlled trial conceals 0067 6.1 Improvement of the Stuttering of a Patient the drug type until the conclusion of the trial. During the trial Treated with Pagoclone. all patients are taking 0.01 mg pagoclone/kg body weight/ 0068 A 26-year old female patient is enrolled in a day. Each group is provided a pharmaceutically effective clinical trial examining the efficacy and Safety of pagoclone, daily dose of one of the eight Second active agents, and one US 2005/0256029 A1 Nov. 17, 2005 group is provided a placebo. The patients have never before (b) R is selected from the group of Substituents consisting experienced relief of Stuttering from a medication. During of: alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, the trial, both the patients and the clinicians treating them in alkoxyalkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoy the clinical trial monitor the Stuttering by a battery of loxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoy objective criteria, and document each case. lamino, alkenoylamino, alkoxycarbonyl, alkenoxycar bonyl, alkoxycarbonylamino, alkoxycarbonylarninoalkyl, aryl, cycloalkyl having 3 to What is claimed is: 6 ring members, cycloalkenyl having 4 to 6 ring 1. A method for alleviating Stuttering, in a Subject in need members, cycloalkylalkyl having 3 to 6 ring members, thereof, comprising: cycloalkenylalkyl having 4 to 6 ring members, with the administering a therapeutically effective dose of a proviso that each of the foregoing R. Substituents has gamma-aminobutyric acid receptor modulator, its phar up to 8 carbon atoms, trifluoromethyl, nitro, amino, maceutically acceptable salts, enantiomers, or metabo hydroxyl, halogen, aminocarbonyl, cyano, cyanoalkyl lites thereof. having from 2 to 4 carbon atoms, aminocarbonylalkyl 2. The method according to claim 1, having 2 to 4 carbon atoms, aryl, alkaryl, piperazinyl, wherein said modulator comprises: allopregnanolone, and methyl-piperazinyl; alphaxalone, alprozolam, amobarbital, aprobarbital, (c) X and X are the same or different sterically compat avermectin B, itbaclofen, bicuculline, butabarbital, ible substituents which are selected from the group but albital, camazepam, cloflubicyne, chlordiazep consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, oxide, clorazepam, chloraZepate, diazepam, diazepam alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, binding inhibitory protein, diazepam binding inhibitory alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, protein fragment, dihydroepiandrosterone, epiallopreg alkylthio, alkanoylamino, alkenoylamino, alkoxycar nanolone, estazolam, etbicuphat, etbicythionat, etomi bonyl, alkenoxycarbonyl, alkoxycarbonylamino, date, flucybene, flunitrazepam, flurazepam, halazepam, alkoxycarbonylaminoalkyl, aryl, cycloalkyl having 3 to D-B-hydrastine, isobicyphat, lorazepam, mebicyphat, 6 ring members, cycloalkenyl having 4 to 6 ring mephobarbital, methohexital, midazolam, oxazepam, members, cycloalkylalkyl having 3 to 6 ring members, pagoclone, pentobarbitone, pentobarbital, phenobar cycloalkenylalkyl having 4 to 6 ring members, with the bital, picrotoxinin, picrotin, pinazepam, prazepam, additional proviso that each of the foregoing X and X pregnanolone, pregnenolone, progesterone, propofol, Substituents has up to 8 carbon atoms, trifluoromethyl, propylbicyphat, quazepam, 2-(7-chloro-2-naphthyri nitro, amino, hydroxyl, halogen, aminocarbonyl, din-1,8-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one, cyano, cyanoalkyl having from 2 to 4 carbon atoms, 2-(7-chloro-2-naphthyridin-1,8-yl)isoindolin-1-yl-4- aminocarbonylalkyl having 2 to 4 carbon atoms, and acetamidobutyrate, 2-(7-chloro-1,8-naphthyridin-2yl)- (d) X is selected from the group consisting of: a meth 3-(5-methyl-5-hydroxy-2-oxohexyl)-1-isoindolinone, ylene;-C(HR)- where R is selected from the group secobarbital, Suriclone, tenazepam, tetrahydrodeoxy of substituents consisting of alkyl, alkenyl, alkynyl, corticosterone, tetramethylene Sulfotetramido, thiopen alkoxy, alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alk tal, triazolam, Zopiclone, pharmaceutically acceptable enoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkyl salts thereof, enantiomers thereof, or metabolites sulfinyl, alkylthio, alkanoylamino, alkenoylamino, thereof. alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbony 3. The method according to claim 1, wherein the modul lamino, alkoxycarbonylaminoalkyl, aryl, cycloalkyl lator has the formula (I): having 3 to 6 ring members, cycloalkenyl having 4 to 6 ring members, cycloalkylalkyl having 3 to 6 ring members, cycloalkenylalkyl having.4 to 6 ring mem (I) bers, with the additional proviso that each of the O foregoing R. Substituents has up to 8 carbon atoms, X1 N=yR, trifluoromethyl, nitro, amino, hydroxyl, halogen, arni nocarbonyl, cyano, cyanoalkyl having from 2 to 4 N carbon atoms, and aminocarbonylalkyl having 2 to 4 ( X ( , 2) carbon atoms; amino; -N(Rs)- where Rs is Selected from the group of Substituents consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkoxy alkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoylamino, alkenoylamino, alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, wherein: cycloalkyl having 3 to 6 ring members, cycloalkenyl (a) R and R are the same or different sterically compat having 4 to 6 ring members, cycloalkylalkyl having 3 ible substituents which are selected from the group to 6 ring members, cycloalkenylalkyl having 4 to 6 ring consisting of: hydrogen; alkyl having 1 to 8 carbon members, with the additional proviso that each of the atoms; alkyl having 1 to 8 carbon atoms, and having at foregoing Rs Substituents has up to 8 carbon atoms, least one of nitrogen, oxygen, Sulfur, or phosphorus, trifluoromethyl, nitro, amino, hydroxyl, halogen, ami aryl having 1 to 8 carbon atoms, and aryl having 1 to nocarbonyl, cyano, cyanoalkyl having from 2 to 4 8 carbon atoms and having at least one nitrogen, carbon atoms, and aminocarbonylalkyl having 2 to 4 oxygen, Sulfur, or phosphorus; carbon atoms; Sulfur, phosphorus; and oxygen group; US 2005/0256029 A1 Nov. 17, 2005

pharmaceutically acceptable Salts thereof, enantiomers acceptable Salts, enantiomers, metabolites, or combi thereof, or metabolites thereof. nations thereof, and a Second active ingredient. 4. The method according to claim 3, wherein R and R 23. The pharmaceutical composition according to claim are covalently bonded to form a polycyclic Structure. 22, wherein Said gamma-aminobutyric acid receptor modu 5. The method according to claim 3, wherein the lator is formula I: cycloalkyl of R, R, Rs, X, and X are the same or different, and each have up to 3 alkyl Substituents. 6. The method according to claim 3, wherein the cycloalk (I) enyl of R, R, Rs, X, and X are the same or different, and O each have up to 3 alkyl Substituents. 7. The method according to claim 3, wherein the N M cycloalkylalkyl of R, R, Rs, X, and X are the same or different and each have up to 3 alkyl substituents. X ( , ) 8. The method according to claim 3, wherein the cycloalk X3 enylalkyl of R, R, Rs, X, and X are the same or different and each have up to 3 alkyl Substituents. o={ 9. The method according to claim 3, wherein X and X R3 are covalently bonded to. form a polycyclic Structure. 10. The method according to claim 1, additionally com wherein: prising a pharmaceutically acceptable carrier. (a) R and R2 are the same or different sterically compat 11. The method according to claim 1, wherein Said ible Substituents which are Selected from the group modulator is effective at the receptor Subtype A. consisting of hydrogen; alkyl having 1 to 8 carbon 12. The method according to claim 1, wherein Said atoms, alkyl having 1 to 8 carbon atoms, and having at modulator is an agonist of the receptor Subtype A. least one of nitrogen, oxygen, Sulfur, or phosphorus, 13. The method according to claim 1, wherein said administration is performed parenterally, orally, vaginally, aryl having 1 to 8 carbon atoms, and aryl having 1 to rectally, nasally, buccally, intravenously, intramuscularly, 8 carbon atoms and having at least one nitrogen, Subcutaneously, intrathecally, epidurally, transdermally, Oxygen, Sulfur, or phosphorus, intracerebroventricularly, or combinations thereof. (b) R is selected from the group of Substituents consisting 14. The method according to claim 1, wherein Said of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, modulator comprises a cyclopyrrolone. alkoxyalkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoy loxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoy 15. The method according to claim 1, wherein the dose is lamino, alkenoylamino, alkoxycarbonyl, alkenoxycar about 0.01 to about 1000 mg. bonyl, alkoxycarbonylamino, 16. The method according to claim 15, wherein the dose alkoxycarbonylaminoalkyl, aryl, cycloalkyl having 3 to is about 0.1 mg to about 10 mg. 6 ring members, cycloalkenyl having 4 to 6 ring 17. The method according to claim 2, wherein said members, cycloalkylalkyl having 3 to 6 ring members, modulator comprises pagoclone, Suriclone, Zopiclone, 2-(7- cycloalkenylalkyl having 4 to 6 ring members, with the chloro-2-naphthyridin-18-yl)-3-(5-methyl-2-oxohexyl proviso that each of the foregoing R. Substituents has )isoindolin-1-one, 2-(7-chloro-2-naphthyridin-18-yl)isoin up to 8 carbon atoms, trifluoromethyl, nitro, amino, dolin-1-yl-4-acetamidobutyrate, 2-(7-chloro-1.8- hydroxyl, halogen, aminocarbonyl, cyano, cyanoalkyl naphthyridin-2yl)-3-(5-methyl-5-hydroxy-2-oxohexyl)-1- having from 2 to 4 carbon atoms, aminocarbonylalkyl isolindolinone, pharmaceutically acceptable Salts thereof; having 2 to 4 carbon atoms, aryl, alkaryl, piperazinyl, enantiomers thereof, or metabolites thereof. and methyl-piperazinyl; 18. The method according to claim 17, wherein the modulator comprises pagoclone. (c) X and X- are the same or different Sterically compat 19. The method according to claim 18, wherein the ible Substituents which are Selected from the group pagoclone is administered at least once daily. consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, 20. The method according to claim 1, wherein the subject alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, is Suffering from Stuttering, motor tic, clonic Stuttering, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, dysfluency, Speech blockage, dysarthria, Tourette's Syn alkylthio, alkanoylamino, alkenoylamino, alkoxycar drome, or logospasm. bonyl, alkenoxycarbonyl, alkoxycarbonylamino, 21. A method of alleviating Stuttering, in a Subject in need alkoxycarbonylaminoalkyl, aryl, cycloalkyl having 3 to thereof, comprising: 6 ring members, cycloalkenyl having 4 to 6 ring members, cycloalkylalkyl having 3 to 6 ring members, administering a therapeutically effective dose of a cycloalkenylalkyl having 4 to 6 ring members, with the gamma-amino butyric acid receptor modulator, phar additional proviso that each of the foregoing X and X maceutically acceptable Salts thereof, enantiomers Substituents has up to 8 carbon atoms, trifluoromethyl, thereof, or metabolites thereof, and a Second active nitro, amino, hydroxyl, halogen, aminocarbonyl, ingredient. cyano, cyanoalkyl having from 2 to 4 carbon atoms, 22. A pharmaceutical composition for alleviating Stutter aminocarbonylalkyl having 2 to 4 carbon atoms, and ing, in a Subject in need thereof, comprising: (d) X is selected from the group consisting of: a meth a therapeutically effective amount of a gamma-aminobu ylene, -C(HR)- where R is selected from the group tyric acid receptor modulator, its pharmaceutically of Substituents consisting of alkyl, alkenyl, alkynyl, US 2005/0256029 A1 Nov. 17, 2005 10

alkoxy, alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alk 26. The composition according to claim 23, wherein the enoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkyl cycloalkenyl of R, R, Rs, X, and X each have up to 3 Sulfinyl, alkylthio, alkanoylamino, alkenoylamino, alkyl Substituents. alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbony lamino, alkoxycarbonylaminoalkyl, aryl, cycloalkyl 27. The composition according to claim 23, wherein the having 3 to 6 ring members, cycloalkenyl having 4 to cycloalkylalkyl of R, R, Rs, X, and X each have up to 3 6 ring members, cycloalkylalkyl having 3 to 6 ring alkyl Substituents. members, cycloalkenylalkyl having 4 to 6 ring mem 28. The composition according to claim 23, wherein the bers, with the additional proviso that each of the cycloalkenylalkyl of R, R, Rs, X, and X each have up to foregoing R. Substituents has up to 8 carbon atoms, 3 alkyl substituents. trifluoromethyl, nitro, amino, hydroxyl, halogen, ami nocarbonyl, cyano, cyanoalkyl having from 2 to 4 29. The composition according to claim 23, wherein X carbon atoms, and aminocarbonylalkyl having 2 to 4 and X are covalently bonded to form a polycyclic structure. carbon atoms; amino; -N(Rs)- where Rs is selected 30. The pharmaceutical composition according to claim from the group of Substituents consisting of alkyl, 23 wherein formula I is a cyclopyrrolone. alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkoxy 31. The pharmaceutical composition according to claim alkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoylamino, 30, wherein the cyclopyrrolone comprises pagoclone, Suri alkenoylamino, alkoxycarbonyl, alkenoxycarbonyl, clone, Zopiclone, 2-(7-chloro-2-naphthyridin-18-yl)-3-(5- alkoxycarbonylamino, alkoxycarbonylaminoalkyl, methyl-2-oxohexyl)isoindolin-1-one, 2-(7-chloro-2-naph cycloalkyl having 3 to 6 ring members, cycloalkenyl thyridin-18-yl)isoindolin-1-yl-4-acetamidobutyrate, 2-(7- having 4 to 6 ring members, cycloalkylalkyl having 3 chloro-1.8 -naphthyridin-2yl)-3-(5-methyl-5-hydroxy-2- to 6 ring members, cycloalkenylalkyl having 4 to 6 ring oxohexyl)-1-isoindolinone, pharmaceutically acceptable members, with the additional proviso that each of the Salts thereof, enantiomers thereof, metabolites thereof, or foregoing Rs Substituents has up to 8 carbon atoms, combinations thereof. trifluoromethyl, nitro, amino, hydroxyl, halogen, ami nocarbonyl, cyano, cyanoalkyl having from 2 to 4 32. The pharmaceutical composition according to claim carbon atoms, and aminocarbonylalkyl having 2 to 4 30, wherein Said cyclopyrrolone comprises pagoclone. carbon atoms, Sulfur, phosphorus, and oxygen group; 33. A method for alleviating Stuttering, in a Subject in need pharmaceutically acceptable Salts thereof, enantiomers thereof, comprising: thereof, or metabolites thereof. 24. The composition according to claim 23, wherein R administering a dose of pagoclone in a pharmaceutically and R2 are covalently bonded to form a polycyclic structure. acceptable carrier, where the pagoclone is present in an 25. The composition according to claim 23, wherein the amount between about 0.1 mg and about 10 mg. cycloalkyl of R, R, Rs, X, and X each have up to 3 alkyl Substituents.