WO2001008670A2 - Methodes et compositions destinees a attenuer le begaiement - Google Patents

Methodes et compositions destinees a attenuer le begaiement Download PDF

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Publication number
WO2001008670A2
WO2001008670A2 PCT/US2000/020402 US0020402W WO0108670A2 WO 2001008670 A2 WO2001008670 A2 WO 2001008670A2 US 0020402 W US0020402 W US 0020402W WO 0108670 A2 WO0108670 A2 WO 0108670A2
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Prior art keywords
carbon atoms
ring members
substituents
alkyl
stuttering
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PCT/US2000/020402
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English (en)
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WO2001008670A3 (fr
Inventor
John J. Murphy
Kay Jorgenson D'orlando
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Interneuron Pharmaceuticals, Inc.
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Priority to AU63810/00A priority Critical patent/AU6381000A/en
Publication of WO2001008670A2 publication Critical patent/WO2001008670A2/fr
Publication of WO2001008670A3 publication Critical patent/WO2001008670A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to methods for treating stuttering.
  • the invention also relates to pharmaceutical compositions for treating stuttering, comprising gamma-aminobutyric acid modulators and pharmaceutically acceptable salts thereof, including the cyclopyrrolones, notably pagoclone [(+)2-(7-chloro-l,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-l-isoindolinone], alone or in combination with one or more pharmaceutically active agents, and a pharmaceutically acceptable carrier.
  • Stuttering is a poorly understood condition marked by frequent repetitions or prolongations of sounds, and an impaired fluency of speech.
  • Accessory features of stuttering possibly resulting from the attempts of the stutterer to control the stuttering, include blocks in the flow of speech sounds, swallowing, grimacing, tremors of the jaw and tongue, coughing, rapid eye blinking, and jerking movements of the arm or upper trunk. (Brady, J. Am J Psychiatry, 1991, 148, 1309).
  • One form, developmental stuttering often appears in early human childhood or adolescence, and affects predominantly males. An estimated three million Americans are affected and the condition is not dependent on language type or cultural background.
  • a less frequent type is neurogenic stuttering, often a result of head trauma or stroke. Subtle differences between neurogenic and developmental dysfluency may be observed, for example in the repetitive reading test, where sufferers of developmental stuttering often improve by the tenth reading of a passage, but sufferers of neurogenic stuttering do not.
  • a third type is drug-induced stuttering, an increasingly frequent problem.
  • stutterers have been treated by a wide variety of methods devised by some of the best minds of the time. Both Hippocrates and Hieronymus Merculialis recommended oral or head surgeries or mutilations.
  • psychiatric treatments have been tried ranging from operant reinforcement to psychotherapy for presumed unconscious conflicts. However, those who stutter are remarkably well-adjusted, and are similar to those who do not stutter in personality traits. Current methods include speech training and pharmaceutical intervention. The improvement for patients, unfortunately, has been limited.
  • GABA gamma- aminobutyric acid
  • GABA appears to function mainly at two types of receptors, termed GABA A and GABA B receptors, that have different structures.
  • the GABA A receptor is a GABA-gated chloride ion channel and the GABA B receptor is a G-protein coupled regulator of potassium conductance.
  • GABA receptors can be modulated by several classes of pharmacologic agents, notably the benzodiazepines, the barbiturates, convulsants, and neurosteroids of the class epiallopregnanolone or epalons. These classes of agents appear to act at different, discrete sites on the GABA A receptor.
  • TBPS t-butyl- bicyclophosphorothionate
  • Partial agonists can be efficacious in producing some effects, e.g., anxiolysis, in common with full agonists, but may be less effective in producing others, e.g., sedation.
  • Antagonists, or "blockers,” on the other hand counteract the action of endogenous GABA and exogenous agonists. Inverse agonists decrease the inherent or constitutive stimulation by a receptor in the absence of an agonist.
  • Modulator is a term that includes agonist, partial agonist, inverse agonist, antagonist, neurotransmitter, reuptake inhibitor, and degradation inhibitor.
  • Antagonists are often relatively specific to a particular class of agonists.
  • flumazenil a benzodiazepine antagonist
  • blocks the function of benzodiazepines including flunitrazepam, diazepam, pinazepam, prazepam, halazepam, camazepam, and flurazepam.
  • GABA A receptor modulators especially agonists and partial agonists, are also known to act as antiphobics, myorelaxants, anti-epileptics, and by other means.
  • GABA A receptor modulators act as myorelaxants by decreasing muscle stiffness, decreasing tonus, and reducing voluntary muscle contraction in spasticity. Also some GABA A modulators have hypnotic, sleep-inducing, amnestic, sedative, and/or anti-convulsant effects. Antagonists of GABA A receptor function tend to block these effects and may even be anxiogenic or proconvulsant in some individuals.
  • GABA A agonists in particular the benzodiazepines and the cyclopyrrolones, act to reduce anxiety and induce a sense of calm. In consequence, these agents are termed anxiolytics. It has long been thought that anxiety is a component of stuttering, although the cellular bases for anxiety and stuttering are not at all clear. In contrast, however, the results of placebo-controlled studies of benzodiazepines on stuttering have been inconsistent and disappointing (Brady, supra).
  • the present invention relates to a method for alleviating stuttering, which comprises administering a preparation including an effective amount of one or more GABA receptor modulators. It is an object of the invention to provide a method for alleviating stuttering, which comprises administering a therapeutical ly effective dose of a preparation selected from the class of benzodiazepines. Use of active metabolites, active enantiomers, active racemic mixtures, or pharmaceutically acceptable salts of benzodiazepines, as an anti-stuttering medication is contemplated.
  • the class of cyclopyrrolones includes, but is in no way limited to, pagoclone, suriclone (4-methyl- 1 -piperazinecarboxylic acid 6-(7-chloro-l,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-
  • pagoclone, its active metabolite, its active enantiomer, an active racemic mixture comprising pagoclone, or pharmaceutically acceptable salts thereof are contemplated as an anti-stuttering medication.
  • the present invention is useful for treating, alleviating or preventing stuttering.
  • the stuttering can be characterized as being developmental, neurogenic or drug-induced stuttering.
  • stuttering is understood to include common stuttering, motor tic, clonic stuttering, dysfluency, speech blockage, impaired phonation, dysarthria, Tourette's syndrome, developmental stuttering, neurogenic stuttering, drug-induced stuttering, logospasm, and the like.
  • the present invention also contemplates a pharmaceutical composition suitable for alleviating stuttering in a person afflicted with stuttering which comprises (i) at least one GABA A receptor modulator, active enantiomer, active metabolite, or pharmaceutically acceptable salt thereof; (ii) at least a second pharmaceutically active agent; and (iii) a pharmaceutically acceptable carrier.
  • the invention relates to a pharmaceutical composition
  • a GABA A modulator including but not limited to pagoclone; suriclone (4-methyl- 1 -piperazinecarboxylic acid 6- (7-chloro-l,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-7-oxo-5H-l,4-dithiino[2,3-c]pyrrol-5-yl ester); zopiclone (4-methyl- 1 -piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H- pyrrolo-[3.4]pyrazin-5-yl ester); 2-(7-chloro-l,8-naphthyridin-2-yl)-3-(5-methyl-5-hydroxy-2- oxohexyl)-l-isoindolinone, their active enantiomers
  • a further object of the invention relates to administration of independent pharmaceutical preparations to the same patient at the same time or different times, preferably at about the same time, and by the same or different modes of administration, where one pharmaceutical preparation comprises a GABA A receptor modulator and the second pharmaceutical preparation comprises a different agent.
  • the present invention contemplates a method of alleviating stuttering in a person, comprising administering an effective stuttering alleviating amount of at least one GABA receptor modulator, an enantiomer of the modulator, an active metabolite of the modulator, or a pharmaceutically acceptable salt of the modulator.
  • One embodiment is a GABA receptor modulator effective at the receptor subtype A.
  • a method of the present invention includes the treatment of the developmental stuttering and dysfluency that manifests itself, commonly, in adolescence or childhood.
  • Another method of the present invention includes the treatment of stuttering and dysfluency that can occur after trauma to head and body tissues, e.g., those resulting from surgery, injuries, etc.
  • 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 embodiment.
  • any mode of administration may be used. It is preferred, however, that the mode of administration is selected from parenteral, oral, vaginal, rectal, nasal, buccal, intravenous, intramuscular, subcutaneous, intrathecal, epidural, intracerebroventricular, transdermal, or combinations thereof.
  • the GABA A receptor modulator, enantiomer of the modulator, active metabolite of the modulator, or pharmaceutically acceptable salt of the modulator can act in the central nervous system, including spinal cord, or in the peripheral nervous system, the neuro-muscular system or elsewhere. These agents can have transient action, sustained action or persistent action.
  • agents active at GABA A receptors are suitable for use in the present invention, including cyclopyrrolones, benzodiazepines, general anesthetics, barbiturates, and, neurosteroids, alone or in combination.
  • Suitable components are: allopregnanolone, alphaxalone, alprozolam, amobarbital, aprobarbital, avermectin B, ⁇ baclofen, bicuculline, butabarbital, butalbital, camazepam, cloflubicyne, chlordiazepoxide.
  • clorazepam chlorazepate, diazepam, diazepam binding inhibitory protein, diazepam binding inhibitory protein fragment, dihydroepiandrosterone, epiallopregnanolone, estazolam, etbicuphat, etbicythionat, etomidate, flucybene, flunitrazepam, flurazepam, halazepam, D- ⁇ -hydrastine, isobicyphat, lorazepam, mebicyphat, mephobarbital, methohexital, midazolam, oxazepam, pagoclone, pentobarbitone, pentobarbital, phenobarbital, picrotoxinin, picrotin, pinazepam, prazepam, pregnanolone, pregnenolone, progesterone, propofol, propylbicyphat, quazepam, 2-(7
  • the present invention provides a new method of treatment of stuttering using pharmaceutical compounds that preferentially modulate GABA A receptors.
  • the useful compounds of the invention are cyclopyrrolones according to Formula I, metabolites thereof, enantiomers thereof, racemates thereof, and salts including acid addition salts thereof, alone or in conjunction with one or more other therapeutic agents: wherein:
  • Ri and R 2 are the same or different sterically compatible substituents which are selected from the group consisting of: hydrogen; alkyl having 1 to 8 carbon atoms; alkyl having 1 to 8 carbon atoms, and having at least one of nitrogen, oxygen, sulfur, or phosphorus; aryl having 1 to 8 carbon atoms; and aryl having 1 to 8 carbon atoms and having at least one nitrogen, oxygen, sulfur, or phosphorus;
  • R is selected from the group of substituents consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoylamino, alkenoylamino, alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aryl, aryl, cycloalkyl 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 members, with the proviso that each of the foregoing R 3 substituents has up to 8 carbon atoms, trifluor acid
  • Xi and X 2 are the same or different sterically compatible substituents which are selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoylamino, alkenoylamino, alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aryl, cycloalkyl 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 members, with the additional proviso that each of the foregoing X
  • X3 is selected from the group consisting of: a methylene; — C(HR ) — where R 4 is selected from the group of substituents consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoylamino, alkenoylamino, alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aryl, cycloalkyl 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 members, with the additional pro
  • the Ri and R 2 substituents can be on positions 3, 4, 5, or 6 of the ring.
  • the invention includes compounds having the structural formula I and the acid addition salts thereof.
  • the pharmaceutically acceptable acid addition salts are preferred.
  • the pharmaceutically acceptable acid addition salts are those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and as such, they are the pharmacological equivalents of the bases having the foregoing structural formulas.
  • the salts have physical properties which make them more desirable for pharmaceutical formulation purposes such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substances may be used for pharmaceutical purposes.
  • Acid addition salts which do not meet the foregoing criteria for pharmaceutical acceptability, for instance as to toxicity, are sometimes useful as intermediates for isolation and purification of the present substances or for other chemical synthetic purposes such as separation of optical isomers. Such salts are also part of the invention.
  • the acid addition salts are made by reaction of a base of the structural formula I with the acid, preferably by contact in solution. They also are made by metathesis or treatment with an anion exchange resin whereby the anion of one salt of the substance is replaced by another anion under conditions which allows for separation of the undesired species such as by precipitation from solution or extraction into a solvent or elution from or retention on an anion exchange resin.
  • acids for the purposes of salt formation include hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, phosphoric, nitric, mucic, isethionic, methanesulfonic, p-toluenesulfonic, glucosaccharic, palmitic, heptanoic, oxalic, cyclamic, succinic, malic, fumaric, mandelic, malonic, and others.
  • the compounds of the present invention shown by the structural formula I contain an asymmetric carbon atom in the cyclopyrrolone ring and occur as optically active isomers as well as racemic mixtures thereof.
  • the present invention is intended to include each of the optically pure, optically active and racemic forms.
  • Some of the substances of the present invention contain an asymmetric carbon atom in the Xi, X 2 , Ri, R 2 , or R 3 substituents in formula I, and diastereoisomeric pairs of racemates exist. These forms are also contemplated and included in the methods of the present invention.
  • optically active isomers of the foregoing compounds is carried out, for example, by forming a salt with an optically active acid many of which are known to those skilled in the art such as optically active tartaric, mandelic, cholic, O,0-di-p-toluoyl tartaric, and 0,0-dibenzoyl tartaric acids, or other acids conventionally employed for this purpose. Separation of optical isomers can be accomplished as disclosed in United States Patent 4,960,779 which is incorporated herein by reference.
  • the compound is mixed with a solid, pulverulent carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin, as well as with glidents such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like and pressed into tablets.
  • a solid, pulverulent carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin
  • glidents such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like
  • the above prepared core is coated with a concentrated solution of sugar, which solution may contain e.g., gum arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets are coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents and if desired, dye is added to this coating.
  • a concentrated solution of sugar which solution may contain e.g., gum arabic, gelatin, talc, titanium dioxide or the like.
  • the tablets are coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents and if desired, dye is added to this coating.
  • Hard gelatin capsules consisting of gelatin and e.g., glycerine and the like, the active ingredient is mixed with a vegetable oil and encapsulated in conventional manner.
  • Hard gelatin capsules may contain granules of the active ingredient in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starch (such as e.g. potato starch, corn starch, or amylopectin), cellulose derivatives or gelatin.
  • a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starch (such as e.g. potato starch, corn starch, or amylopectin), cellulose derivatives or gelatin.
  • Dose units for rectal administration may be prepared in the form of suppositories containing the compound in a mixture with a neutral fat base, or in the form of a gelatin-rectal capsule with a mixture of vegetable oil or paraffin oil.
  • Liquid preparations suitable for oral administration are suspensions, syrups and elixirs containing from about 0.2% by weight to about 20% by weight of the active ingredient.
  • a suitable injectible composition is comprised of an aqueous solution of a water soluble pharmaceutically acceptable acid addition salt adjusted to physiologically acceptable pH.
  • the present invention relates to a pharmaceutical composition for alleviating stuttering, which comprises: (a) an effective amount of a first active ingredient, which comprises at least one GABA A receptor modulator, including, but not limited to the cyclopyrrolone class of agents, enantiomers, metabolites, and pharmaceutically acceptable salts thereof; optionally, (b) an effective amount of a second active agent; and optionally (c) a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • pharmaceutically acceptable carrier solid or liquid filler, diluent, or encapsulating substance, which may be safely used in systemic or topical administration.
  • pharmaceutically acceptable carriers including solid or liquid fillers, diluents, hydrotropies, surface active agents, and encapsulating substances.
  • the amount of a carrier employed in conjunction with the GABA A receptor modulator is sufficient toO provide practical quantity of material per unit dose of GABA A receptor modulator.
  • compositions of the invention include sugar, starches, cellulose, vegetable oils, mineral oils, buffers, polyols, alginic acid and the like. Specific pharmaceutically acceptable carriers are described in U.S. Pat. No. 4,401,663; European Patent Application No. 089710; and European
  • Patent Application No. 0068592 which are incorporated herein by reference.
  • Carriers for parenteral administration may include propylene glycol, pyrrolidone, ethyl oleate, aqueous ethanol and combinations thereof.
  • Still other representative carriers include acacia, agar, alginates, hydroxyalkylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, carrageenan, powdered cellulose, guar gum, cholesterol, gelatin, gum agar, gum arabic, gum karaya, gum ghatti, locust bean gum, octoxynol-9, oleyl alcohol, pectin, poly(acrylic acid) and its homologs, polyethylene glycol, polyvinyl alcohol, polyacrylamide, sodium lauryl sulfate, poly(ethylene oxide), polyvinylpyrrolidone, glycol monostearate, propylene glycol monostearate, xanthan gum, tragacanth, sorbitan esters, stearyl alcohol, starch and its modifications. Suitable ranges vary from about 1% to about 50%) by weight of the total composition.
  • Preferred GABA A receptor modulators are cyclopyrrolones, including, but not limited to, pagoclone; zopiclone; suriclone; 2-(7-chloro-2-naphthyridin-l,8-yl)-3-(5- methyl-2- oxohexyl)isoindolin- 1 -one, 2-(7-chloro-2-naphthyridin- 1 ,8-yl)isoindolin- 1 -yl-4- acetamidobutyrate, 2-
  • GABA A modulators suitable for use in the present invention can exist as salts.
  • the compounds of the invention can form acid addition salts of pharmaceutically acceptable inorganic or organic acids.
  • suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, or nitric acid.
  • suitable organic acids include, but are not limited to, aliphatic or aromatic carboxylic or sulfonic acids, for example, acetic, propionic, succinic, glycolic, lactic, fumaric, tartaric, tannic, gluconic, citric, ascorbic, maleic, pyruvic, palmoic, oxalic, dioxalic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p- toluenesulfonic, or naphthalenesulfonic acid.
  • Preferred salts include the hydrochloride, oxalate, fumarate, citrate, tannate, or dioxalate salts.
  • the pharmaceutical composition of the present invention can have a wide range of GABA A receptor modulator dosage where a total dosage of about 0.01 to about 1000 mg is administered daily.
  • this dosage is about 0.1 mg to about 10 mg.
  • the frequency of doses can vary from about one per day to about two per hour.
  • the dosage can also be adjusted for body weight, from about 0.001 mg/ kg body weight/ day to about 1.0 mg/ kg body weight/ day.
  • the administration of the GABA A receptor modulator can be by intravenous, intramuscular, subcutaneous, intrathecal, epidural, or intracerebroventricular injection, or parenterally, orally, vaginally, rectally, nasally, buccally, transdermally, and combinations thereof.
  • the administration of the stuttering alleviating or ameliorating substance to the patient can be conducted in conjunction with treatment for other ailments with the second active agent, or other agents.
  • Effective dosage levels can vary widely; actual amounts will depend on the agents used and the state and diagnosis of the patient being treated. As those skilled in the art would recognize, many factors that modify the action of the stuttering alleviating composition and second active agents herein will be taken into account by the treating physician including, but not limited to, such factors as age, body weight, sex, diet and condition of the patient, time of administration, rate and route of administration, psychiatric condition, other diseases, and so forth. Titration of dosage for individual patients, up to the maximal dose permits attainment of functionally effective doses.
  • Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage determination tests in view of experimental data provided herein.
  • the stuttering alleviating substance of the instant invention will ordinarily be formulated with one or more pharmaceutically acceptable ingredients in accordance with known and acceptable practice.
  • the stuttering alleviating substance can be formulated as a liquid, powder, aerosol, elixir, injectable solution, etc.
  • Formulations for oral use can be provided as hard gelatin capsules wherein the stuttering alleviating substance is mixed with an inert solid diluent such as calcium carbonate, phosphate, or kaolin or, preferably, as soft gelatin capsules wherein the stuttering alleviating substance is mixed with an oleaginous medium, e.g., liquid paraffin or soybean oil.
  • an inert solid diluent such as calcium carbonate, phosphate, or kaolin
  • an oleaginous medium e.g., liquid paraffin or soybean oil.
  • Aqueous suspensions can contain the stuttering alleviating substance in an admixture with pharmaceutically acceptable excipients such as: suspending agents, like carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia; dispersing or wetting agents such as naturally occurring phosphatide, e.g., lecithin; or condensation products of an alkaline oxide with fatty acids, e.g., polyoxyethylene stearate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, e.g., polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monooleate.
  • pharmaceutically acceptable excipients such as: suspending agents, like carboxymethylcellulose, methylcellulose, hydroxy
  • Such aqueous suspensions can also contain one or more preservatives, e.g., ethyl or n-propyl-p- hydroxybenzoate; or one or more coloring agents, flavoring agents and sweetening agents such as saccharose, saccharin or sodium or calcium cyclamate.
  • preservatives e.g., ethyl or n-propyl-p- hydroxybenzoate
  • coloring agents, flavoring agents and sweetening agents such as saccharose, saccharin or sodium or calcium cyclamate.
  • aqueous suspensions water is added to dispersible powders and granules to provide the stuttering alleviating substance in an admixture with dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
  • Additional excipients include sweetening, flavoring and coloring agents.
  • Syrups and elixirs can be formulated with sweetening agents such as glycerol, sorbitol or sucrose. Such formulations can contain demulcent, preservative, flavoring and coloring agents.
  • the stuttering alleviating agent can be administered in a sustained release formulation.
  • Methods for sustained release dosage forms are advantageously provided in U.S. Pat. Nos. 4,788,055; 4,816,264; 4,828,836; 4,834,965; 4,834,985; 4,996,047; 5,071,646; and 5,133,974, which are incorporated herein by reference.
  • compositions of the invention have pharmacological advantages that render them useful for alleviating stuttering.
  • at least one GABA receptor modulator and one or more second active agent may be administered according to any convenient or effective method for introducing foreign substances into the blood stream of mammals, such as by oral, rectal, nasal, buccal, vaginal or parenteral routes.
  • the effective dose levels may be administered on a regimen of about 1 to about 6 times a day.
  • the pharmaceutical formulation of the invention can be in dosage forms such as pills, capsules, powders or granules for oral administration.
  • the compounds can be conveniently administered in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, supra, 1451- 1459, 1504-1512, 1519-1570, and 1615-1693, which are incorporated herein by reference.
  • compositions can be prepared into pharmaceutical compositions of an admixture with pharmaceutically acceptable carriers.
  • the compositions may be prepared for use by or in parenteral, that is, subcutaneous, intramuscular, or intravenous, administration, particularly in the form of liquid suspensions.
  • the composition can be prepared for oral administration, particularly in the form of tablets or capsules, or intranasally, particularly in the form of powders, nasal drops or aerosols.
  • the composition can also be prepared for use in vaginal or rectal administration.
  • Formulations for parenteral administration may contain as common excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for vaginal or rectal administration may contain as excipients, for example, polyalkylene glycols such as polyethylene glycol, petroleum jelly, cocoa butter and the like.
  • Formulations for inhalation administration may be solid and contain excipients, for example, lactose, or may be aqueous or oily solutions for administration in the form of nasal drops.
  • typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch and the like.
  • a pharmaceutically acceptable composition can be formed by incorporation of any of the normally employed excipients, oral dose extenders or carriers such as for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate and the like.
  • Such compositions can take the form of solution, suspension, tablets, pills, capsules, powders, sustained release formulations and the like.
  • the active substances are combined with, e.g., solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch, amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycol of suitable molecular weight to form tablets or dragee cores.
  • the latter are coated, e.g., with concentrated sugar solutions which can also contain, e.g., gum arabic, talcum, titanium dioxide, or with lacquer dissolved in a mixture of solvents.
  • Other suitable oral dosage units are hard gelatin capsules as well as soft, closed capsules from a gelatin softener such as glycerol.
  • dosage units for rectal administration are suppositories that comprise a combination of at least one GABA A receptor modulator, one or more second active agents and a carrier suppository foundation.
  • suppositories that comprise a combination of at least one GABA A receptor modulator, one or more second active agents and a carrier suppository foundation.
  • a gelatin rectal capsules which contain a combination of at least one of the above substances with polyethylene glycol of suitable molecular weight as carrier.
  • Ampoules for parenteral, particularly intramuscular and also intravenous administration preferably contain at least one GABA A receptor modulator and one or more second active agents. If necessary, suitable stabilizing agents and/or buffer substances are added to the ampule solutions. These compounds can be encapsulated, tableted or prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, sesame oil, vegetable oil, mineral oil, soybean oil, cottonseed oil, glycerin, saline, ethanol, and water.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • the preparation is in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • a liquid formulation can be administered directly by mouth or filled into a soft gelatin capsule. 5.
  • Patients with stuttering problems are enrolled in a clinical trial examining the efficacy and safety of pagoclone and a second active agent in the treatment of developmental stuttering.
  • the second agents are ibuprofen, UTI Plus, propanolol, minoxidil, estrogen, citicoline, ergotamine, and pregnanolone.
  • Patients are randomly assigned to one of nine groups.
  • the double- blind placebo-controlled trial conceals the drug type until the conclusion of the trial.
  • all patients are taking 0.01 mg pagoclone/ kg body weight/ day.
  • Each group is provided a pharmaceutically effective daily dose of one of the eight second active agents, and one group is provided a placebo.
  • the patients have never before experienced relief of stuttering from a medication.
  • both the patients and the clinicians treating them in the clinical trial monitor the stuttering by a battery of objective criteria, and document each case.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement du bégaiement qui consistent à traiter les personnes concernées avec des modulateurs du récepteur de l'acide gamma-aminobutyrique (GABA). Des énantiomères actifs, des métabolites actifs et des sels pharmaceutiquement acceptables des modulateurs du récepteur de l'acide gamma-aminobutyrique, dont les cyclopyrrolones, sont des composants acceptables des compositions. Parmi les modulateurs de la classe des cyclopyrrolones figurent la pagoclone, la suriclone, la zopiclone, 2-(7-chloro-2-naphthyridin-1, 8-yl)-3-(5-méthyl-2-oxohexyl)isoindolin-1-one, 2-(7-chloro-2-naphthyridin-1,8-yl)isoindolin-1-yl-4-acétamidobutyrate, et 2-(7-chloro-1,8-naphthyridin-2yl)-3-(5-méthyl-5-hydroxy-2-oxohexyl)-1-isoindolinone.
PCT/US2000/020402 1999-07-29 2000-07-27 Methodes et compositions destinees a attenuer le begaiement WO2001008670A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1254660A2 (fr) * 2001-04-30 2002-11-06 Warner-Lambert Company Méthodes, kits et compositions pour utiliser dérivés à structure pyrrolique contre l'anxiété
US7776345B2 (en) 2001-07-04 2010-08-17 Sun Pharma Advanced Research Company Ltd Gastric retention controlled drug delivery system
US20160159781A1 (en) * 2013-08-05 2016-06-09 Syngenta Participations Ag Chemical compounds
US9457033B2 (en) 2011-02-15 2016-10-04 Socpra Sciences Et Genie, S.E.C. Steroid alkaloids and uses thereof as antimicrobial agents against electron transport-deficient microbes and as potentiators for antimicrobial agents against pathogenic bacteria
US9687496B2 (en) 2010-01-14 2017-06-27 Asarina Pharma Ab Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties
JP2020506182A (ja) * 2017-02-10 2020-02-27 アサリナ ファーマ アーベー 医学的治療における使用のための３−β−ヒドロキシ−５−α−プレグナン−２０−オン

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EP1254660A3 (fr) * 2001-04-30 2003-03-26 Warner-Lambert Company Méthodes, kits et compositions pour utiliser dérivés à structure pyrrolique contre l'anxiété
AU783516B2 (en) * 2001-04-30 2005-11-03 Warner-Lambert Company Methods, kits and compositions for using pyrrole derivatives
US7026332B2 (en) 2001-04-30 2006-04-11 Indevus Pharmaceuticals, Inc. Methods of treating obsessive-compulsive disorder
EP1642576A3 (fr) * 2001-04-30 2007-01-10 Indevus Pharmaceuticals, Inc. Méthodes, kits et compositions pour utiliser dérivés à structure pyrrolique contre l'anxiété
US7553847B2 (en) 2001-04-30 2009-06-30 Indevus Pharmaceuticals, Inc. Use of pagoclone for the treatment of social anxiety disorder
EP1254660A2 (fr) * 2001-04-30 2002-11-06 Warner-Lambert Company Méthodes, kits et compositions pour utiliser dérivés à structure pyrrolique contre l'anxiété
US7776345B2 (en) 2001-07-04 2010-08-17 Sun Pharma Advanced Research Company Ltd Gastric retention controlled drug delivery system
US8012496B2 (en) 2001-07-04 2011-09-06 Sun Pharma Advanced Research Company Ltd. Gastric retention controlled drug delivery system
US11534446B2 (en) 2010-01-14 2022-12-27 Asarina Pharma Ab Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties
US9687496B2 (en) 2010-01-14 2017-06-27 Asarina Pharma Ab Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties
US9457033B2 (en) 2011-02-15 2016-10-04 Socpra Sciences Et Genie, S.E.C. Steroid alkaloids and uses thereof as antimicrobial agents against electron transport-deficient microbes and as potentiators for antimicrobial agents against pathogenic bacteria
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US11026954B2 (en) 2017-02-10 2021-06-08 Asarina Pharma Ab 3-beta-hydroxy-5-alpha-pregnan-20-one for use in medical treatment
JP2022159475A (ja) * 2017-02-10 2022-10-17 アサリナ ファーマ アーベー 医学的治療における使用のための３－β－ヒドロキシ－５－α－プレグナン－２０－オン
JP7179739B2 (ja) 2017-02-10 2022-11-29 アサリナ ファーマ アーベー 医学的治療における使用のための３－β－ヒドロキシ－５－α－プレグナン－２０－オン

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