WO2012094612A1 - Method of treating essential tremor - Google Patents

Method of treating essential tremor Download PDF

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Publication number
WO2012094612A1
WO2012094612A1 PCT/US2012/020515 US2012020515W WO2012094612A1 WO 2012094612 A1 WO2012094612 A1 WO 2012094612A1 US 2012020515 W US2012020515 W US 2012020515W WO 2012094612 A1 WO2012094612 A1 WO 2012094612A1
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Prior art keywords
group
compound
administered
imidazo
spiro
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PCT/US2012/020515
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French (fr)
Inventor
Eckard Weber
Tilman Oltersdorf
Martin Koller
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Zenyaku Kogyo Kabushikikaisha
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Publication of WO2012094612A1 publication Critical patent/WO2012094612A1/en

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention is directed to the use of a therapeutically effective amount of a heterocyclic compound or a pharmaceutically acceptable salt thereof to treat essential tremor.
  • the compound ST101 also know as ZSET1446, has shown pharmacological activity in rodent models of learning and memory relevant to AD after both acute (single-dose) and chronic administration.
  • the chemical name for ST101 is spiro(imidazo(l ,2-a)pyridin-2(3H)-one-3,2'-indan).
  • ST101 has been shown to increase acetylcholine (ACh) levels in rodent brains and to improve learning and memory in a number of behavioral tests in animals.
  • ACh acetylcholine
  • LTP long-term potentiation
  • CaMK II Ca 2+ /calmodulin-dependent protein kinase II
  • ACh increases extracellular ACh concentrations in the cerebral cortex, and increases extracellular concentrations of both ACh and dopamine in the hippocampus.
  • the breadth of models across which ST101 exerts its effects suggests the potential for involvement at an upstream target in the signaling pathway(s) associated with these processes.
  • SAMP8 a mouse strain that develops age-related deficits in learning and memory along with accumulation of ⁇ -like deposits in brain tissue.
  • the SAMP8 mouse is discussed in Morley, J.E., Biogerontology 3: 57-60 (2002).
  • ST101 decreased accumulation of ⁇ -like deposits and also produced an improvement in learning and memory functions, suggesting the behavioral effect of ST101 may be linked to reduction of ⁇ production and/or accumulation. See US Patent Appl. Publication No. 2008/103158 Al .
  • Essential tremor is a slowly progressive neurological disorder identified by an involuntary shaking movement.
  • Current drug treatments of tremors do not offer long- term sustained efficacy but rather lower the severity of the condition.
  • the most common and primarily prescribed treatment is a beta-blocker propranolol and primidone, a drug used to treat seizures.
  • Additional medications that may reduce tremors include antiseizure drugs such as gabapentin and topiramate, mild tranquilizers such as alprazolam and clonazepam, and calcium-channel blockers such as flunarizine and nimodipine. In severe cases, surgery may be used to treat tremors.
  • the present invention provides a method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
  • the compound is spiro(imidazo(l ,2-a)pyridin-2(3H)-one-3,2'-indan).
  • the compound of Formula (I) is administered at a dose of between about 10 mg and 600 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 500 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 400 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 300 mg.
  • the compound of Formula (I) is administered orally to the subject.
  • the compound of Formula (1) is administered parenterally to the subject.
  • the compound of Formula (I) is administered intravenously, subcutaneously, or intramuscularly to the subject.
  • the present invention provides a method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) and a therapeutic agent used to treat essential tremor.
  • the therapeutic agent used to treat essential tremor is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a compound of Formula (I) and (b) a further therapeutic agent for the treatment of essential tremor.
  • the compound of Formula ( ⁇ ) is spiro(imidazo(l ,2-a)pyridin-2(3H)-one-3,2'-indan).
  • the further therapeutic agent for the treatment of essential tremor is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
  • the compound of Formula (I) and the therapeutic agent are administered orally.
  • the present invention provides a kit comprising spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent.
  • the therapeutic agent is selected from the group consisting of propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
  • the therapeutic agent is in a form suitable for oral administration.
  • the present invention provides a kit comprising spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent, wherein spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered simultaneously.
  • the present invention provides a kit comprising spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent, wherein spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered separately.
  • Figure 1 describes the effects of propranolol and ST101 on harmaline-induced tremor events. Events that are significantly different from the vehicle are indicated with a *.
  • Figure 2 describes the effects of propranolol and ST101 on (a) harmaline- induced short tremor events at 30, 60, and 90 minutes after administrations of ST101 and (b) harmaline-induced long tremor events at 30, 60, and 90 minutes after administration of ST101 (* (p ⁇ 0.05 and ** (p ⁇ 0.01) indicate significant differences compared to vehicle for each specific time point).
  • Figure 3 describes the effects of propranolol and ST101 on (a) harmaline- induced total tremor events at 30, 60, and 90 minutes after administration of ST101 (* (p ⁇ 0.05 and ** (p ⁇ 0.01) indicate significant differences compared to vehicle for each specific time point).
  • Figure 4 describes the effects of (a) a 60 minute pre-treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events and (b) a 90 minute pre-treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events (* (p ⁇ 0.05 and ** (p ⁇ 0.01) indicate significant differences compared to vehicle for each specific time point).
  • the present invention is directed to a method of treating or preventing essential tremor comprising administering to a subject in need thereof an effective amount of a heterocyclic compound having the general Formula (I):
  • the structural unit having the general Formula (II) may be one or more structural units selected from multiple types of structural units having the general Formula (III)
  • R x is methyl or nil.
  • Ri and R 2 each are one or more functional groups independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, acetylamino, benzylamino, trifluoromethyl, C)-C6 alkyl, Ci-Ce alkoxy, C 2 -C6 alkenyl, C3-C8 cycloalkyl, benzyloxy, CH 2 -Rs (wherein R5 is phenyl (which may be substituted with Q-Ce alkyl, halogen, or cyano), or thienyl), and -0-(CH 2 ) n -R6, wherein R is a vinyl, C3-C8 cycloalkyl, or phenyl, and n is 0 or 1.
  • R 3 and R4 each are one or more functional groups independently selected from the group consisting of hydrogen, Cj- C 6 alkyl, C2-C6 alkenyl, C 3 -C 8 cycloalkyl, CH2-R5 (wherein R5 is phenyl (which may be substituted with C ⁇ -Ce alkyl, halogen, or cyano), naphtyl, or thienyl), and -CH(Rg)- R 7 .
  • R3 and R4 together form a spiro ring having the general Formula (IV):
  • R 7 is one or more functional groups selected from the group consisting of a vinyl; ethynyl; phenyl optionally substituted by a Ci-C 6 alkyl, Ci-C ⁇ alkoxy, hydroxy, 1 or 2 halogen atoms, di C] -C6 alkylamino, cyano, nitro, carboxy, or phenyl; phenethyl; pyridyl; thienyl; and furyl.
  • the above Rg is a hydrogen or C -C alkyl.
  • the structural unit B may be one or more structural units selected from multiple types of structural units having the general Formula (V).
  • the structural unit B binds at a position marked by * in the general Formula (V) to form a spiro ring.
  • R • go is on,e o -rO more fu ( n V ct ) ional groups selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkoxy, cyano, and trifluoromethyl.
  • the heterocyclic compound having the general Formula (I) has asymmetric carbon atoms in the structure, its isomer from asymmetric carbon atoms and their mixture (racemic modification) is present. In such cases, all of them are included in the heterocyclic compound used in the embodiments described later.
  • the term "Ci-C6 M refers ro 1 to 6 carbon atoms unless otherwise defined.
  • C3-C8 refers to 3 to 8 carbon atoms unless otherwise defined.
  • C1-C6 alkyl includes linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, and n-hexyl.
  • C1-C6 alkoxy includes linear or branched alkoxy groups such as methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, and n-hexyloxy.
  • C3-C8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl, and cyclooctyl.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • heterocyclic compound useful in the practice of the present invention is selected from the group consisting of:
  • the compound is spiro(imidazo(l ,2-a)pyridin-2(3H)- one-3,2'-indan).
  • the method of the present invention can be practiced using any of the compounds disclosed in U.S. Patent Appl. Publication No.
  • the compounds of the present invention can be administered at an effective oral dosage of 0.0005 mg per kilogram of body weight or higher.
  • the compound is administered as part of a unit dosage form containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.
  • compositions for use in this invention include all compositions wherein the active ingredient is contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the active ingredient may be administered to mammals, e.g. humans, orally at a dose of 0.001 to 3 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated.
  • the active ingredient may be administered to mammals, e.g. humans, intravenously or intramuscularly at a dose of 0.001 to 3 mg kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated.
  • Approximately 0.001 to approximately 3 mg/kg can be orally administered to treat or prevent such disorders. If another agent is also administered, it can be administered in an amount winch is effective to achieve its intended purpose.
  • the unit oral dose may comprise from approximately 0.001 to approximately
  • the unit dose may be administered one or more times daily as one or more tablets, each containing from approximately 0.1 to approximately 90 mg, conveniently approximately 10 to 180 mg of the composition or its solvates.
  • the unit oral dose can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100°, 110, 120, 130, 140, 150, 160, 170, or 180 mg.
  • the dose is between about 10 mg and 600 mg, between about 10 mg and 500 mg, between about 10 mg and 400 mg, or between about 10 mg and 300 mg. In another embodiment, the dose is 270 mg, 360 mg, 450 mg, or 540 mg.
  • the active ingredient may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
  • the active ingredient may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredient into preparations that can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredient into preparations that can be used pharmaceutically.
  • the preparations particularly those preparations, which can be administered orally, such as tablets, dragees, and capsules, and also preparations, which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, can contain from approximately 0.01 to 99 percent, or from approximately 0.25 to 75 percent of active ingredient, together with the excipient.
  • the compounds of the invention can be in the form of hydrate or acid addition salts as a pharmaceutically acceptable salt.
  • Possible acid addition salts include inorganic acid salts such as the hydrochloride, sulfate, hydrobromide, nitrate, and phosphate salts and organic acid salts such as acetate, oxalate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and salicylate salts.
  • inorganic acid salts such as the hydrochloride, sulfate, hydrobromide, nitrate, and phosphate salts
  • organic acid salts such as acetate, oxalate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate, me
  • Acid addition salts are formed by mixing a solution of the particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, lactic acid, tartaric acid, carbonic acid, phosphoric acid, sulfuric acid, oxalic acid, and the like.
  • Basic salts are formed by mixing a solution of the particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl- glucamine and the like.
  • compositions of the invention may be administered to any animal or "subject,” which may experience the beneficial effects of the active ingredient.
  • subject animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, inhalation, or topical routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present invention are manufactured in a manner, which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid excipients, optionally grinding the resultant mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular: fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g. maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates e.g. tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch paste, using, e.g. maize starch, wheat starch, rice starch, potato starch
  • disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl- starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active ingredient doses.
  • Other pharmaceutical preparations which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredient in the form of granules, which may be mixed with fillers, such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredient can be dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, e.g. suppositories, which consist of a combination of one or more of the active ingredients with a suppository base.
  • Suitable suppository bases are, e.g. natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active ingredient with a base.
  • Possible base materials include, e.g. liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active ingredient in water-soluble form, e.g. water-soluble salts and alkaline solutions.
  • suspensions of the active ingredient as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, e.g. sesame oil; or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides or polyethylene glycol-400.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension include, e.g. sodium carboxymethyl cellulose, sorbitol, and or dextran.
  • the suspension may also contain stabilizers.
  • oral pharmaceutical preparations comprise an enteric coating.
  • enteric coating is used herein to refer to any coating over an oral pharmaceutical dosage form that inhibits dissolution of the active ingredient in acidic media, but dissolves rapidly in neutral to alkaline media and has good stability to long-term storage.
  • the dosage form having an enteric coating may also comprise a water soluble separating layer between the enteric coating and the core.
  • the core of the enterically coated dosage form comprises an active ingredient.
  • the core also comprises pharmaceutical additives and/or excipients.
  • the separating layer may be a water soluble inert active ingredient or polymer for film coating applications.
  • the separating layer is applied over the core by any conventional coating technique known to one of ordinary skill in the art. Examples of separating layers include, but are not limited to sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, polyvinyl acetal diethylaminoacetate and hydroxypropyl methylcellulose.
  • the enteric coating is applied over the separating layer by any conventional coating technique.
  • enteric coatings include, but are not limited to cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymers of methacrylic acid and methacrylic acid methyl esters, such as Eudragit ® L 12,5 or Eudragit ® L 100 (Rohm Pharma), water based dispersions such as Aquateric (FMC Corporation), Eudragit L 100-55 (Rohm Pharma) and Coating CE 5142 (BASF), and those containing water soluble plasticizers such as Citroflex ® (Pfizer).
  • the final dosage form is an enteric coated tablet, capsule or pellet.
  • Examples of prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g. those obtained by condensation with a CI -4 alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g. those obtained by condensation with a C carboxylic acid, C3.6 dioic acid or anhydride thereof (e.g. succinic and fumaric anhydrides according to methods known in the art); imines of amino containing compounds (e.g. those obtained by condensation with a C aldehyde or ketone according to methods known in the art); and acetals and ketals of alcohol containing compounds (e.g. those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).
  • carboxylic acid containing compounds e.g. those obtained by condensation with a CI -4 alcohol according to methods known in the art
  • esters of hydroxy containing compounds e.g. those obtained by condensation with a C carboxy
  • an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
  • the method of the present invention can be used with other therapeutic agents commonly used to treat essential tremor.
  • Other therapeutic agents used include the beta-blocker propranolol, primidone, anti-seizure drugs such as gabapentin and topiramate, mild tranquilizers such as alprazolam and clonazepam, and calcium- channel blocks such as flunarizine and nimodipine.
  • mice Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (0.1 , 1, or 10 mg/kg) and placed in separate holding cages. After 20 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. After habituation, tremor activity of the mice was measured for approximately 8 minutes. The recorded frequencies (1 -64 hertz) of activity and the number of tremor events were captured electronically.
  • mice Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (1, 10, or 30 mg/kg) and placed in separate holding cages. After 20 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. After habituation, tremor activity of the mice was measured for approximately 8 minutes. Mice were re-tested again at 40 and 70 minutes post-harmaline injection for a total of 3 trials eact (10, 40, and 70 minute time points). During the test trials, the recorded frequencies (1 -64 hertz) of activity and the number of tremor events were captured electronically.
  • mice Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (1 , 10, or 30 mg/kg) and placed in separate holding cages. After 50 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. Following habituation (60 minutes after initial injection), tremor activity of the mice was measured for approximately 8 minutes. During the test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.
  • mice Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg kg), or ST101 (1, 10, or 30 mg kg) and placed in separate holding cages. After 80 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. Following habituation (90 minutes after initial injection), tremor activity of the mice was measured for approximately 8 minutes. During the test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.

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Abstract

The present invention is directed to the use of a therapeutically effective amount of a heterocyclic compound or a pharmaceutically acceptable salt thereof to treat essential tremor.

Description

METHOD OF TREATING ESSENTIAL TREMOR
BACKGROUND OF THE INVENTION
Field Of The Invention
[0001] The present invention is directed to the use of a therapeutically effective amount of a heterocyclic compound or a pharmaceutically acceptable salt thereof to treat essential tremor.
Related Art
[0002] The compound ST101, also know as ZSET1446, has shown pharmacological activity in rodent models of learning and memory relevant to AD after both acute (single-dose) and chronic administration. The chemical name for ST101 is spiro(imidazo(l ,2-a)pyridin-2(3H)-one-3,2'-indan).
[0003] ST101 has been shown to increase acetylcholine (ACh) levels in rodent brains and to improve learning and memory in a number of behavioral tests in animals. (Yamaguchi Y., et al., J. Pharmacol. Exp. Ther. 577:1079-87 (2006); Ito Y., et al, J. Pharmacol. Exp. Ther. 320:819-27 (2007)). This functional improvement was correlated with enhancement in long-term potentiation (LTP), the electrophysiological correlate of memory formation, as well as with biochemical changes that are associated with enhanced LTP, such as increased activity of protein kinase C and Ca2+/calmodulin-dependent protein kinase II (CaMK II) (Han, F., et al., J. Pharmacol. Exp. Ther. 326: 127-134 (2008)). To date, the molecular target of ST101 is not known.
[0004] Experiments have shown that ST101 potentiates nicotine-stimulated release of
ACh, increases extracellular ACh concentrations in the cerebral cortex, and increases extracellular concentrations of both ACh and dopamine in the hippocampus. The breadth of models across which ST101 exerts its effects suggests the potential for involvement at an upstream target in the signaling pathway(s) associated with these processes.
[0005] ST101 has also demonstrated effects in the Senescence Accelerated Mouse P 8
(SAMP8), a mouse strain that develops age-related deficits in learning and memory along with accumulation of Αβ-like deposits in brain tissue. The SAMP8 mouse is discussed in Morley, J.E., Biogerontology 3: 57-60 (2002). ST101 decreased accumulation of Αβ-like deposits and also produced an improvement in learning and memory functions, suggesting the behavioral effect of ST101 may be linked to reduction of Αβ production and/or accumulation. See US Patent Appl. Publication No. 2008/103158 Al .
|0006] Essential tremor is a slowly progressive neurological disorder identified by an involuntary shaking movement. Current drug treatments of tremors do not offer long- term sustained efficacy but rather lower the severity of the condition. The most common and primarily prescribed treatment is a beta-blocker propranolol and primidone, a drug used to treat seizures. Additional medications that may reduce tremors include antiseizure drugs such as gabapentin and topiramate, mild tranquilizers such as alprazolam and clonazepam, and calcium-channel blockers such as flunarizine and nimodipine. In severe cases, surgery may be used to treat tremors.
[0007] Thus, there is a clear need for an effective, low risk therapy for essential tremor.
BRIEF SUMMARY OF THE INVENTION
[0008] In one embodiment, the present invention provides a method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein Ri, R2, R3, R , and Rx are as defined herein. In another embodiment, the compound is spiro(imidazo(l ,2-a)pyridin-2(3H)-one-3,2'-indan).
[0009] In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 600 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 500 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 400 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 300 mg.
[0010] In another embodiment, the compound of Formula (I) is administered orally to the subject. In another embodiment, the compound of Formula (1) is administered parenterally to the subject. In another embodiment, the compound of Formula (I) is administered intravenously, subcutaneously, or intramuscularly to the subject.
[0011] In another embodiment, the present invention provides a method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) and a therapeutic agent used to treat essential tremor. In another embodiment, the therapeutic agent used to treat essential tremor is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
[0012] In another embodiment, the present invention provides a pharmaceutical composition comprising (a) a compound of Formula (I) and (b) a further therapeutic agent for the treatment of essential tremor. In one embodiment, the compound of Formula (Γ) is spiro(imidazo(l ,2-a)pyridin-2(3H)-one-3,2'-indan). In another embodiment, the further therapeutic agent for the treatment of essential tremor is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
[0013] In another embodiment, the compound of Formula (I) and the therapeutic agent are administered orally.
[0014] In another embodiment, the present invention provides a kit comprising spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent. In one embodiment, the therapeutic agent is selected from the group consisting of propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine. In another embodiment, the therapeutic agent is in a form suitable for oral administration.
[0015] In another embodiment, the present invention provides a kit comprising spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent, wherein spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered simultaneously.
[0016] In another embodiment, the present invention provides a kit comprising spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent, wherein spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered separately.
BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES [0017] Figure 1 describes the effects of propranolol and ST101 on harmaline-induced tremor events. Events that are significantly different from the vehicle are indicated with a *.
[0018] Figure 2 describes the effects of propranolol and ST101 on (a) harmaline- induced short tremor events at 30, 60, and 90 minutes after administrations of ST101 and (b) harmaline-induced long tremor events at 30, 60, and 90 minutes after administration of ST101 (* (p<0.05 and ** (p<0.01) indicate significant differences compared to vehicle for each specific time point).
[0019] Figure 3 describes the effects of propranolol and ST101 on (a) harmaline- induced total tremor events at 30, 60, and 90 minutes after administration of ST101 (* (p<0.05 and ** (p<0.01) indicate significant differences compared to vehicle for each specific time point).
[0020] Figure 4 describes the effects of (a) a 60 minute pre-treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events and (b) a 90 minute pre-treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events (* (p<0.05 and ** (p<0.01) indicate significant differences compared to vehicle for each specific time point).
DETAILED DESCRIPTION OF THE INVENTION
[0021 ] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the invention belongs.
[0022] The present invention is directed to a method of treating or preventing essential tremor comprising administering to a subject in need thereof an effective amount of a heterocyclic compound having the general Formula (I):
Figure imgf000006_0001
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.
[0023] In the general Formula (I), the structural unit having the general Formula (II)
Figure imgf000007_0001
may be one or more structural units selected from multiple types of structural units having the general Formula (III)
Figure imgf000007_0002
[0024] In the general Formula (I), Rx is methyl or nil. In the general Formula (I) and
Formula (II), Ri and R2 each are one or more functional groups independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, acetylamino, benzylamino, trifluoromethyl, C)-C6 alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C3-C8 cycloalkyl, benzyloxy, CH2-Rs (wherein R5 is phenyl (which may be substituted with Q-Ce alkyl, halogen, or cyano), or thienyl), and -0-(CH2)n-R6, wherein R is a vinyl, C3-C8 cycloalkyl, or phenyl, and n is 0 or 1.
[0025] In the general Formula (I) and Formula (II), R3 and R4 each are one or more functional groups independently selected from the group consisting of hydrogen, Cj- C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, CH2-R5 (wherein R5 is phenyl (which may be substituted with C\-Ce alkyl, halogen, or cyano), naphtyl, or thienyl), and -CH(Rg)- R7. Alternatively, R3 and R4 together form a spiro ring having the general Formula (IV):
Figure imgf000008_0001
[0026] R7 is one or more functional groups selected from the group consisting of a vinyl; ethynyl; phenyl optionally substituted by a Ci-C6 alkyl, Ci-C^ alkoxy, hydroxy, 1 or 2 halogen atoms, di C] -C6 alkylamino, cyano, nitro, carboxy, or phenyl; phenethyl; pyridyl; thienyl; and furyl. The above Rg is a hydrogen or C -C alkyl.
[0027] Furthermore, in the general Formula (IV), the structural unit B may be one or more structural units selected from multiple types of structural units having the general Formula (V). The structural unit B binds at a position marked by * in the general Formula (V) to form a spiro ring.
Figure imgf000008_0002
[0028] R •go is on,e o -rO more fu (nVct)ional groups selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkoxy, cyano, and trifluoromethyl. [0029] When the heterocyclic compound having the general Formula (I) has asymmetric carbon atoms in the structure, its isomer from asymmetric carbon atoms and their mixture (racemic modification) is present. In such cases, all of them are included in the heterocyclic compound used in the embodiments described later. |0030] The term "Ci-C6M refers ro 1 to 6 carbon atoms unless otherwise defined. The term "C3-C8" refers to 3 to 8 carbon atoms unless otherwise defined. The term "C1-C6 alkyl" includes linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, and n-hexyl. The term "C1-C6 alkoxy" includes linear or branched alkoxy groups such as methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, and n-hexyloxy. The term "C3-C8 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl, and cyclooctyl. The term "halogen" includes fluorine, chlorine, bromine, and iodine.
[0031] In another embodiment, the heterocyclic compound useful in the practice of the present invention is selected from the group consisting of:
3,3-dimethylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dipropylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibutylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-diallylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-diallyl-8-benzyloxyimidazo(l,2-a)pyridin-2(3H)-one,
3,3-di(2-propinyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-diberi2yl-8-methylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzyl-5,7-dimemylirnidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzyl-8-hydroxyimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzyl-8-methoxyimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzyl-8-ethoxyimidazo(l,2-a)pyridin-2(3H)-one,
8-allyloxy-3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzyl-8-isopropoxyimidazo(l,2-a)pyridin-2(3H)-one,
3 ,3 -dibenzyl-8-cyclopropylmethyloxyimidazo(l,2-a)pyridin-2(3 H)-one, 3,3-dibenzyl-8-cycloheptyloxyimidazo(l,2-a)pyridin-2(3H)-one, 3,3-dibenzyl-6-chloroimidazo(l,2-a)pyridin-2(3H)-one,
3,3-diberizyl-6,8-dichloroimidazo(l,2-a)pyridin-2(3H)-one, 3,3-dibenzyl-8-chloro-6-trifluoromethylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzyl-8-benzyloxyimidazo(l,2-a)pyridin-2(3H)-one,
8-amino-3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,
8-acetylamino-3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibenzyl-8-benzylaminoimidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(3-chlorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(3-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(2,4-dichlorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-dnnethylaminobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-methoxybenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-biphenylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-cyanobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-hydroxy-benzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(3-phenyl-l-propyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(2,4-difluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-nitrobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(4-carboxybenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
8-benzyloxy-3,3-bis(l-phenylethyl)imidazo(l,2-a)pyridin-2(3H)-one,
8-benzyloxy-3,3-bis(3-methylbenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
8-benzyloxy-3,3-bis(4-methylbenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3-benzyl-3-(4-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
3-ethyl-3(4-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,
8-methyl-3,3-bis(3-pyridylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,
8-methyl-3,3-bis(4-pyridylmethyl)imidazo(l,2-a)pyridin-2(3H)-one3
3,3-bis(2-thienylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(2-furylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,
spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-indan),
spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(2,3)dihydrophenarene), spiro(imidazo(2,l-b)thiazol-6(5H)-one-5,2'-benzo(f)indan),
spiro(imidazo(l,2-b)thiazol-6(5H)-one-5,2'-indan),
spiro(2-methylimidazo(1.2-b)thiazol-6(5H)-one-5,2'-benzo(f)indan),
5,5-bis(4-fluorobenzyl)imidazo(2,l-b)thiazol-6(5H)-one. 5,5-dibenzylimidazo(2,l-b)thiazol-6(5H)-one,
5,5-bis(4-methylbenzyl)imidazo(2,l-b)thiazol-6(5H)-one,
5,5-bis(4-cyanobenzyl)imidazo(2,l-b)thiazol-6(5H)-one,
5,5-dibenzyl-2-methylimidazo(2,l-b)thiazol-6(5H)-one,
5,5-bis(4-fluorobenzyl)-2-methylimidazo(2,l-b)thiazol-6(5H)-one,
5,5-dicyclohexyl-2-methylimidazo(2,l-b)thiazol-6(5H)-one;
5,5-bis(4-cyanobenzyl)-2-methylimidazo(2,l-b)thiazol-6(5H)-one,
5,5-di(2-butenyl)imidazo(2,l-b)thiazol-6(5H)-one,
5,5-dibutylimidazo(2,l-b)thiazol-6(5H)-one,
5,5-dicyclohexylimidazo(2.1-b)thiazol-6(5H)-one,
5,5-bis(2-thienylmethyl)imidazo(2,l-b)thiazol-6(5H)-one,
spiro(2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one-5,2'-benzo(f)indan),
5,5-dibutyl-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,
5,5-di(2-butenyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,
5,5-bis(4-methylbenzyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,
5,5-bis(2-thienylmethyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,
5,5-bis(4-fluorobenzyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,
5,5-dibenzyl-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,
spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-benzo(f)indan),
2- hydroxy-3-(2-naphthylmethyl)-imidazo(l,2-a)pyridine,
3- benzylimidazo(l,2-a)pyridin-2(3H)-one,
spiro(5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one-3,2'-benzo(f)indan)J
3,3-dicyclohexyl-5,6)7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one,
3,3-bis(2-thienylmethyl)-5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dibutyl-5)6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one,
3,3-dipropyl-5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one, spiro(imidazo(l,2-a)pyrimidin-2(3H)-one-3,2'-benzo(f)indan),
3 ,3 -di(2-buteny l)imidazo(l,2-a)pyrimidin-2(3 H)-one,
3 -bis(2-thienylrnethyl)imidazo(1.2-a)pyrimidin-2(3H)-one,
3,3-bis(4-fluorobenzyl)imidazo(l,2-a)pyrimidin-2(3H)-one,
3,3-dicyclohexylimidazo(l,2-a)pyrimidin-2(3H)-one,
3,3-bis(4-cyanobenzyl)imidazo(l,2-a)pyrimidin-2(3H)-one,
3,3-bis(4-methylbenzyl)imidazo(l,2-a)pyrimidin-2(3H)-one, 4,4-dibeiizyl-l-methyl-5-oxo-4,5-dihydroimidazole,
spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(4'-fluoroindan)), spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(5'-methoxyindan)), spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(5'-iodoindan)),
spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(4'-cyanoindan)), spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3,2'-indan),
spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-((l,2,5-thiadiazo)(4,5-c)indan)), spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3,2'-((l,2,5-thiadiazo)(4,5- c)indan)),
spiro(imidazo(l,2-a)pyrimidin-2(3H)-one-3,4'-(l -cyclopentene)), spiro(imidazo(l,2-a)pyrimidin-2(3 H)-one-3 ,2 -indan),
spiro(imidazo(l,2-a)pyrimidin-2(3H)-one-3,2'-((l,2,5-thiadiazo)(4,5-c)indan)), spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(5'-trifluoromethylindan)), spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-benzo(e)indan),
spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3,r-(3'-cyclopentene)), spiro(8-benzyloxyimidazo(l,2-a)pyridin-2(3H)-one-3,r-(3'-cyclopentene)), spiro(7,8,9,10-tetrahydroimidazo(2,l-a)isoquinolin-2(3H)-one-3,l'- cyclopentane),
spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3,l'-cyclopentane), and spiro(5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one-3,2'-indan).
[0032] In another embodiment, the compound is spiro(imidazo(l ,2-a)pyridin-2(3H)- one-3,2'-indan). In another embodiment, the method of the present invention can be practiced using any of the compounds disclosed in U.S. Patent Appl. Publication No.
2008/0103157, U.S. Patent Appl. Publication No. 2008/0103158, U.S. Patent No.
6,635,652, and U.S. Patent No. 7,141 ,579, each of which is incorporated by reference in its entirety.
[0033] The compounds of the present invention can be administered at an effective oral dosage of 0.0005 mg per kilogram of body weight or higher. In one embodiment, the compound is administered as part of a unit dosage form containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.
[0034] Compositions for use in this invention include all compositions wherein the active ingredient is contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the active ingredient may be administered to mammals, e.g. humans, orally at a dose of 0.001 to 3 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated. The active ingredient may be administered to mammals, e.g. humans, intravenously or intramuscularly at a dose of 0.001 to 3 mg kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated. Approximately 0.001 to approximately 3 mg/kg can be orally administered to treat or prevent such disorders. If another agent is also administered, it can be administered in an amount winch is effective to achieve its intended purpose.
[0035] The unit oral dose may comprise from approximately 0.001 to approximately
200 mg, or approximately 0.5 to approximately 180 mg of the composition of the invention. The unit dose may be administered one or more times daily as one or more tablets, each containing from approximately 0.1 to approximately 90 mg, conveniently approximately 10 to 180 mg of the composition or its solvates. In one embodiment, the unit oral dose can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100°, 110, 120, 130, 140, 150, 160, 170, or 180 mg.
[0036] In another embodiment, the dose is between about 10 mg and 600 mg, between about 10 mg and 500 mg, between about 10 mg and 400 mg, or between about 10 mg and 300 mg. In another embodiment, the dose is 270 mg, 360 mg, 450 mg, or 540 mg.
[0037] In a topical formulation, the active ingredient may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
[0038] In addition to administering the active ingredient as a raw chemical, the active ingredient may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredient into preparations that can be used pharmaceutically. The preparations, particularly those preparations, which can be administered orally, such as tablets, dragees, and capsules, and also preparations, which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, can contain from approximately 0.01 to 99 percent, or from approximately 0.25 to 75 percent of active ingredient, together with the excipient. [0039] The compounds of the invention can be in the form of hydrate or acid addition salts as a pharmaceutically acceptable salt. Possible acid addition salts include inorganic acid salts such as the hydrochloride, sulfate, hydrobromide, nitrate, and phosphate salts and organic acid salts such as acetate, oxalate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and salicylate salts.
[0040] Acid addition salts are formed by mixing a solution of the particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, lactic acid, tartaric acid, carbonic acid, phosphoric acid, sulfuric acid, oxalic acid, and the like. Basic salts are formed by mixing a solution of the particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl- glucamine and the like.
[0041 ] The pharmaceutical compositions of the invention may be administered to any animal or "subject," which may experience the beneficial effects of the active ingredient. Foremost among such subject animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.
[0042] The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, inhalation, or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
[0043] The pharmaceutical preparations of the present invention are manufactured in a manner, which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid excipients, optionally grinding the resultant mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
[0044] Suitable excipients are, in particular: fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g. maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl- starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active ingredient doses.
[0045] Other pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient in the form of granules, which may be mixed with fillers, such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
[0046] Possible pharmaceutical preparations, which can be used rectally include, e.g. suppositories, which consist of a combination of one or more of the active ingredients with a suppository base. Suitable suppository bases are, e.g. natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules, which consist of a combination of the active ingredient with a base. Possible base materials include, e.g. liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
[0047] Suitable formulations for parenteral administration include aqueous solutions of the active ingredient in water-soluble form, e.g. water-soluble salts and alkaline solutions. In addition, suspensions of the active ingredient as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, e.g. sesame oil; or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension include, e.g. sodium carboxymethyl cellulose, sorbitol, and or dextran. Optionally, the suspension may also contain stabilizers.
[0048] Also included within the scope of the present invention are dosage forms of the active ingredient, in which the oral pharmaceutical preparations comprise an enteric coating. The term "enteric coating" is used herein to refer to any coating over an oral pharmaceutical dosage form that inhibits dissolution of the active ingredient in acidic media, but dissolves rapidly in neutral to alkaline media and has good stability to long-term storage. Alternatively, the dosage form having an enteric coating may also comprise a water soluble separating layer between the enteric coating and the core.
[0049] The core of the enterically coated dosage form comprises an active ingredient.
Optionally, the core also comprises pharmaceutical additives and/or excipients. The separating layer may be a water soluble inert active ingredient or polymer for film coating applications. The separating layer is applied over the core by any conventional coating technique known to one of ordinary skill in the art. Examples of separating layers include, but are not limited to sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, polyvinyl acetal diethylaminoacetate and hydroxypropyl methylcellulose. The enteric coating is applied over the separating layer by any conventional coating technique. Examples of enteric coatings include, but are not limited to cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymers of methacrylic acid and methacrylic acid methyl esters, such as Eudragit®L 12,5 or Eudragit®L 100 (Rohm Pharma), water based dispersions such as Aquateric (FMC Corporation), Eudragit L 100-55 (Rohm Pharma) and Coating CE 5142 (BASF), and those containing water soluble plasticizers such as Citroflex® (Pfizer). The final dosage form is an enteric coated tablet, capsule or pellet.
[0050] Examples of prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g. those obtained by condensation with a CI -4 alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g. those obtained by condensation with a C carboxylic acid, C3.6 dioic acid or anhydride thereof (e.g. succinic and fumaric anhydrides according to methods known in the art); imines of amino containing compounds (e.g. those obtained by condensation with a C aldehyde or ketone according to methods known in the art); and acetals and ketals of alcohol containing compounds (e.g. those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).
[0051] As used herein an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
[0052] The method of the present invention can be used with other therapeutic agents commonly used to treat essential tremor. Other therapeutic agents used include the beta-blocker propranolol, primidone, anti-seizure drugs such as gabapentin and topiramate, mild tranquilizers such as alprazolam and clonazepam, and calcium- channel blocks such as flunarizine and nimodipine.
[0053] Having now generally described this invention, the same will be understood by references to the following examples .which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified. EXAMPLES EXAMPLE 1
Effect of ST101 on harmaline-induccd tremors in mice
[0054] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (0.1 , 1, or 10 mg/kg) and placed in separate holding cages. After 20 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. After habituation, tremor activity of the mice was measured for approximately 8 minutes. The recorded frequencies (1 -64 hertz) of activity and the number of tremor events were captured electronically.
[0055] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 seconds in duration.
[0056] Data were analyzed by analysis of variance (ANOVA) followed by Fisher
PLSD post-hoc analysis. An effect was considered significant if p < 0.05. Statistical outliers that fell above or below 2 standard deviations from the mean were removed from the final analysis.
[0057] The effects of propranolol and ST101 on short, long, and total tremor events are shown in Figure 1. One way analysis of variance (ANOVA) found a significant treatment effect for all tremor measures. Propranolol and ST101 (1 and 10 mg/kg) significantly decreased harmaline induced short, long, and total tremor events. EXAMPLE 2
Time course of effects of ST101 on harmaline-induccd tremors in mice
[0058] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (1, 10, or 30 mg/kg) and placed in separate holding cages. After 20 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. After habituation, tremor activity of the mice was measured for approximately 8 minutes. Mice were re-tested again at 40 and 70 minutes post-harmaline injection for a total of 3 trials eact (10, 40, and 70 minute time points). During the test trials, the recorded frequencies (1 -64 hertz) of activity and the number of tremor events were captured electronically.
[0059] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 seconds in duration.
[0060] Data were analyzed by analysis of variance (ANOVA) followed by Fisher
PLSD post-hoc analysis. An effect was considered significant if p < 0.05. Statistical outliers that fell above or below 2 standard deviations from the mean were removed from the final analysis.
[0061] The effects of propranolol and ST101 on short, long, and total tremor events at
30, 60, and 90 minutes after ST101 (10, 40, and 70 minutes post-harmaline) are shown in Figure 2(a). Two-way repeated measures of ANOVA found significant main effects of treatment and time, and a significant treatment based on time interaction. Propranolol and ST101 (10 and 30 mg/kg) significantly decreased harmaline-induced short tremor events at all three post-harmaline time points as compared to vehicle.
[0062] The effects of propranolol and ST101 on harmaline-induced total (short and long) tremor events at 30, 60, and 90 minutes after ST101 (10, 40, and 70 minutes post-harmaline) are shown in Figure 3. Two-way repeated measures of A OVA found significant main effects of treatment and time, and a significant treatment based on time interaction. Propranolol and ST101 (10 and 30 mg/kg) significantly decreased harmaline-induced total tremor events at all three post-harmaline time points as compared to vehicle. Additionally, the lowest dose of ST101 (1 mg/kg) decreased harmaline-induced total tremor events at 10 and 70 minutes post-harmaline administration.
EXAMPLE 3
Effects of ST101 on harmaline-induced tremors at 60 minutes pre-treatment time
[0063] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (1 , 10, or 30 mg/kg) and placed in separate holding cages. After 50 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. Following habituation (60 minutes after initial injection), tremor activity of the mice was measured for approximately 8 minutes. During the test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.
(0064] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 but less than 0.5 seconds in duration.
[0065] Data were analyzed by analysis of variance (ANOVA) followed by Fisher
PLSD post-hoc analysis. An effect was considered significant if p < 0.05. Statistical outliers that fell above or below 2 standard deviations from the mean were removed from the final analysis.
[0066] The effects of a 60 minute pre-treatment with propranolol or ST101 on short, long, and total tremor events are shown in Figure 4(a). One-way AnOVA found a significant treatment effect for all tremor measurements. Propranolol and ST101 (10 and 30 mg/kg) significantly decreased harmaline-induced short, long, and total tremor events compared to veliicle. The lowest dose of ST101 (1 mg/kg) attenuated long and total tremor events only.
EXAMPLE 4
Effects of ST101 on harmaline-induced tremors at 90 minutes pre-treatment time
[0067] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg kg), or ST101 (1, 10, or 30 mg kg) and placed in separate holding cages. After 80 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. Following habituation (90 minutes after initial injection), tremor activity of the mice was measured for approximately 8 minutes. During the test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.
[0068] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier. Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 but less than 0.5 seconds in duration.
[0069] Data were analyzed by analysis of variance (ANOVA) followed by Fisher
PLSD post-hoc analysis. An effect was considered significant if p < 0.05. Statistical outliers that fell above or below 2 standard deviations from the mean were removed from the final analysis.
[0070] The effects of a 90 minute pre-treatment with propranolol or ST101 on short, long, and total tremor events are shown in Figure 4(b). One-way ANOVA found a significant treatment effect for all tremor measurements. Propranolol and ST101 (10 and 30 mg/kg) significantly decreased harmaline-induced short, long, and total tremor events compared to vehicle. The lowest dose of ST101 (1 mg kg) attenuated long and total tremor events only.
Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications, and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

WHAT IS CLAIMED IS:
1. A method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
Figure imgf000023_0001
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
Rx is methyl or nil;
Ri and R2 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, Ci-Ce alkyl group, Ci-
Ce alkoxy group, C2-C6 alkenyl, C3-C8 cycloalkyl, benzyloxy, CH2-R5, and -O-
(CH2)n-R6;
R3 and R4 are either
(i) each one or more functional groups independently selected from the group consisting of a hydrogen atom, Cj-Ce alkyl group, C2-C6 alkenyl, C3-C8 cycloalkyl group, CH2-R5, and -CH(R«)-R7; or
(ii) R3 and R4 together g of Formula (IV):
Figure imgf000023_0002
(IV)
wherein B may be one or more structural units selected from structural units having the general Formula (V):
Figure imgf000024_0001
the structural unit B binds at a position marked by * in the Formula (V) to form a spiro ring; and
R5 is naphthyl; thienyl; or phenyl, which may be substituted with Ci-Ce alkyl, halogen atom or cyano;
R6 is a vinyl group, C3-C8 cycloalkyl group, or phenyl group, and n is 0 or 1 ;
R7 is one or more functional groups selected from the group consisting of a vinyl group; ethynyl group; phenyl optionally substituted by a Ci-C6 alkyl group, Ci-C6 alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C| -C6 alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;
Rg is a hydrogen atom or Ci-C6 alkyl group; and
R9 is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, Ci-Ce alkoxy group, cyano group, and trifluoromethyl group.
2. The method of claim 1 , wherein the compound is spiro(imidazo(l ,2-a)pyridin-2(3H)- one-3,2'-indan).
3. The method of claim 1 , wherein the compound is administered at a dose of between ' about 10 mg and 600 mg.
4. The method of claim 3, wherein the compound is administered at a dose of between about 10 mg and 500 mg.
5. The method of claim 3, wherein the compound is administered at a dose of between about 10 mg and 400 mg.
6. The method of claim 3, wherein the compound is administered at a dose of between about 10 mg and 300 mg.
7. The method of claim 1, wherein the compound is administered orally to the subject.
8. The method claim 1, wherein the compound is administered parenterally to the subject.
9. The method of claim 1 , wherein the compound is administered intravenously, subcutaneously, or intramuscularly to the subject.
10. The method of claim 1 , further comprising administering a therapeutic agent used to treat essential tremor.
1 1. The method of claim 10, wherein the therapeutic agent is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
12. A pharmaceutical composition comprising: (a) a compound of Formula (I):
Figure imgf000026_0001
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
Rx is methyl or nil;
Ri and R2 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromefhyl group, C1-C6 alkyl group, C\- Ce alkoxy group, C2-C6 alkenyl, C3-Q cycloalkyl, benzyloxy, CH2-Rs, and -O-
(CH2)n- 6;
R3 and R4 are either
(i) each one or more functional groups independently selected from the group consisting of a hydrogen atom, C1-C6 alkyl group, C2-C6 alkenyl, C3-C8 cycloalkyl group, CH2-R5, and -CH(R8)-R7; or
(ii) R3 and R4 together form a spiro ring of Formula (IV):
Figure imgf000026_0002
wherein B may be one or more structural units selected from structural units having the general Formula (V):
Figure imgf000027_0001
the structural unit B binds at a position marked by * in the Formula (V) to form a spiro ring; and
R5 is naphthyl; thienyl; or phenyl, which may be substituted with C1-C6 alkyl, halogen atom or cyano;
R¾ is a vinyl group, C3-C8 cycloalkyl group, or phenyl group, and n is 0 or 1 ;
R7 is one or more functional groups selected from the group consisting of a vinyl group; ethynyl group; phenyl optionally substituted by a C1-C6 alkyl group, Ci-C^ alkoxy group, hydroxy group, 1 or 2 halogen atoms, di Ci-C6 alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;
Rs is a hydrogen atom or Ci-Ce alkyl group; and
R9 is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, Ci-C6 alkoxy group, cyano group, and trifluoromethyl group; and
(b) a further therapeutic agent for the treatment of essential tremor.
13. The pharmaceutical composition of claim 12, wherein the compound of Formula (I) is spiro(midazo(l ,2-a)pyridin-2(3H)-one-3,2'-indan).
14. The pharmaceutical composition of claim 12, wherein the compound of Formula (I) and the therapeutic agent are administered orally.
15. The pharmaceutical composition of claim 12, wherein the therapeutic agent is
propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
16. A kit comprising spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent for the treatment of essential tremor.
17. The kit of claim 16, wherein the therapeutic agent is selected from the group consisting of propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.
18. The kit of claim 16, wherein the therapeutic agent is in a form suitable for oral administration.
19. The kit of claim 16, wherein spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered simultaneously.
20. The kit of claim 16, wherein spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered separately.
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