WO2009054544A1 - Antagonistes des récepteurs ampa pour la maladie de parkinson et les troubles du mouvement - Google Patents

Antagonistes des récepteurs ampa pour la maladie de parkinson et les troubles du mouvement Download PDF

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Publication number
WO2009054544A1
WO2009054544A1 PCT/JP2008/069820 JP2008069820W WO2009054544A1 WO 2009054544 A1 WO2009054544 A1 WO 2009054544A1 JP 2008069820 W JP2008069820 W JP 2008069820W WO 2009054544 A1 WO2009054544 A1 WO 2009054544A1
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pharmaceutically acceptable
hydrate
acceptable salt
optionally substituted
levodopa
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PCT/JP2008/069820
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English (en)
Inventor
Takahisa Hanada
Shigeki Hibi
Kazuki Miyazaki
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Eisai R & D Management Co., Ltd.
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Publication of WO2009054544A1 publication Critical patent/WO2009054544A1/fr

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    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the invention provides pharmaceutical compositions, combinations, and kits comprising AMPA receptor antagonists and methods using AMPA receptor antagonists for treating Parkinson's disease and movement disorders.
  • Parkinson's disease Cardinal features of Parkinson's disease include resting tremor, rigidity, bradykinesia and postural instability. These symptoms are mainly treated with dopaminergic drugs, such as L- DOPA (i.e., 3,4-dihydroxy-L-phenylalanine) and the combination of L-DOPA with decarboxylase inhibitors, dopamine agonists, monoamine oxidase inhibitors, and/or catechol-o- methyltransferase. NMDA-type glutamate receptor antagonists and muscarinic acetylcholine receptor antagonists are also used. Patients with advanced Parkinson's disease also often have parkinsonism and dyskinesia. Amantadine and atypical antipsychotic drugs are used for the treatment of dyskinesia.
  • Other movement disorders include spinocerebellar degeneration, multiple system atrophy, progressive supranuclear palsy, Parkinsonian syndrome, Huntington's disease, Lewy body disease, restless leg syndrome, tardive dyskinesia, tics, Tourette syndrome, dystonia, myoclonus, spasticity, chorea, ballism, ataxia, akathisia, athetosis, rigidity, and tremors. While there is no established protocol for treating these diseases, some drugs have been found to be useful for some of these disease conditions. For example, benzodiazepines are useful for myoclonus, and dystonia. Monoamine-depleting drugs and dopamine antagonists are useful for hyperkinetic disorders like chorea, ballism, and tics.
  • AMPA receptor antagonists include 1,2-dihydropyridine compounds.
  • An exemplary 1,2- dihydropyridine compound is perampanel [i.e., 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2- dihydropyridin-2-one], and is described in US Patent No. 6,949,571.
  • Methods for treating diseases and administering these compounds in conjunction with a cholinesterase inhibitor are described in WO 2006/107859 and WO 2006/107860.
  • Methods for treating diseases and administering these compounds in conjunction with a NMDA receptor antagonist are described in WO 2008/11 1590.
  • the invention provides methods for treatment and/or prophylaxis of Parkinson's disease in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2-dihydropyridine compound), optionally in combination with one or more other active ingredients that are useful for treating Parkinson's disease.
  • the AMPA receptor antagonist is 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2- dihydropyridin-2-one.
  • the methods for the treatment and/or prophylaxis of Parkinson's disease include the treatment and/or prophylaxis of one or more symptoms of Parkinson's disease.
  • the invention provides methods for treatment and/or prophylaxis of movement disorders in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2-dihydropyridine compound).
  • the AMPA receptor antagonist is 3-(2-cyanophenyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2- one.
  • the AMPA receptor antagonist can optionally be administered with one or more other active ingredients that are useful for treating movement disorders.
  • the methods for the treatment and/or prophylaxis of movement disorders include the treatment and/or prophylaxis of one or more symptoms of the movement disorders.
  • the invention provides pharmaceutical compositions, combinations, and kits comprising a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 3-(2- cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one).
  • the pharmaceutical compositions, combinations, and kits can optionally comprise one or more other active ingredients that are useful for treating Parkinson's disease and movement disorders.
  • the present invention relates to the following:
  • a pharmaceutical composition comprising:
  • A an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof;
  • B entacapone/levodopa/carbidopa, entacapone/levodopa/benserazide, pramipexole, tetrabenazine, entacapone, pergolide, ropinirole, bromocriptine, selegiline, ubidecarenone, apomorphine, tolcapone, riluzole, trihexyphenidyl, melevodopa/carbidopa, melevodopa/benserazide, levodopa/carbidopa, levodopa/benserazide, nitisinone, budipine, cabergoline, rotigotine, rasagiline, olanzapine, quetiapine, risperidone, clo
  • composition of (1) wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl- l,2-dihydropyridin-2 -one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
  • composition wherein the composition is used for treating a movement disorder.
  • composition is used for treating one or more symptoms of a movement disorder.
  • a combination comprising:
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci -6 alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-CO-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R 11 J-S(O) n ,-, -S(O) n -N(R 12 )-, -CH 2 -S(O) P -, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -, -N(R
  • A an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and (B) entacapone/levodopa/carbidopa, entacapone/levodopa/benserazide, pramipexole, tetrabenazine, entacapone, pergolide, ropinirole, bromocriptine, selegiline, ubidecarenone, apomorphine, tolcapone, riluzole, trihexyphenidyl, melevodopa/carbidopa, melevodopa/benserazide, levodopa/carbidopa, levodopa/benserazide, nitisinone, budipine, cabergoline, rotigotine, rasagiline, olanzapine, quetiapine, risperidone,
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Cj -6 alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(O) P -, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -, -NN
  • kits comprising the pharmaceutical composition of any one of (1) to (6) or the combination of any one of (7) to (13).
  • a method for treating Parkinson's disease comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (1) to (4) or a therapeutically effective amount of the combination of any one of (7) to (1 1).
  • a method for treating a movement disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (1) to (3), and (5) or a therapeutically effective amount of the combination of any one of (7) to (10), and (12).
  • a method for treating one or more symptoms of a movement disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (1) to (3), and (6) or a therapeutically effective amount of the combination of any one of (7) to (10), and (13).
  • a pharmaceutical composition for treating a movement disorder comprising: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and (C) one or more pharmaceutically acceptable carriers.
  • a pharmaceutical composition for treating one or more symptoms of a movement disorder comprising: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
  • composition of (27) or (28), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (III), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (III) is:
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci -6 alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(0) m -, -S(O) n -N(R 12 )-, -CH 2 -S(O) P -, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -, -N(R 13
  • composition of (27) or (28), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2- dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci -6 alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-CO-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(O) P -, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -, -N(
  • Compounds (A) for use in the treatment of a movement disorder wherein (A) are: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof. (36) Compounds (A) for use in the treatment of one or more symptoms of a movement disorder, wherein (A) are:
  • kits for treating a movement disorder comprising the pharmaceutical composition of any one of (27), (29) and (30).
  • kits for treating one or more symptoms of a movement disorder comprising the pharmaceutical composition of any one of (28) to (30).
  • a method for treating a movement disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (27), (29) and (30).
  • a method for treating one or more symptoms of a movement disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (28) to (30).
  • “Patient” refers to animals, preferably mammals, more preferably humans.
  • the term “patient” includes men and women; and includes adults, children and neonates. In one embodiment, the patient can be an animal companion, such as a dog or a cat.
  • “Active ingredient” refers to the AMPA receptor antagonists and other compounds described herein that are responsible for treatment and/or prophylaxis of a disease or disorder.
  • the active ingredients may have mechanisms of action that are known or unknown, and the active ingredients may have one or more mechanisms of action.
  • the active ingredient may have an asymmetric carbon depending on the type of substituent and may have a stereoisomer (e.g., a geometric isomer, an enantiomer, a diastereomer or the like).
  • the active ingredient or a stereoisomer thereof may form a pharmaceutically acceptable salt.
  • the active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof may be an anhydride, and may form a solvate.
  • the active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a solvate thereof may be crystalline or amorphous. Crystalline polymorphs may exist in the active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a solvate thereof, although not limited thereto and any form of crystal may exist alone or in combination, which. are within the scope of the present invention.
  • Treatment and “treating” refer to the acquisition of a desired pharmacological effect and/or physiologic effect. These effects are prophylactic in terms of completely or partially preventing a disease and/or one or more symptom(s) of the disease, and therapeutic in terms of partially or completely curing a disease and/or one or more symptoms caused by a disease.
  • Treatment and “treating” include any treatment of a disease (e.g., Parkinson's disease, movement disorders) in a patient including, for example: (a) to prevent a disease or one or more symptom(s) of the disease in a patient who is suspected of being predisposed to the disease but not yet been diagnosed as having the disease or who has previously been diagnosed as having the disease but is not currently diagnosed as having the disease; (b) to inhibit one or more symptom(s) of a disease, i.e., to inhibit or delay the progression of one or more of the symptom(s) of the disease; (c) to alleviate one or more symptom(s) of a disease, i.e., to reverse or eliminate one or more symptom(s) of the disease; (d) to reverse the progress of one or more symptom(s) of the disease; or (e) to stabilize one or more symptom(s) of a disease, such that one or more symptom(s) of the disease do not worsen or improve.
  • a disease e.g.
  • administering separately with reference to the administration of two or more compounds to treat and/or prevent and/or delay the onset of the diseases and disorders described herein includes, for example, the sequential administration of the compounds in any order or the simultaneous administration of the compounds.
  • Simultaneous administration of the compounds means that the compounds are administered to the patient at substantially the same time or at exactly the same time, depending on the mode of administration.
  • the sequential administration of the compounds may occur in any order and may occur with any amount of time elapsing between administrations of the compounds. Sequential administration may be based on factors that would influence which of the compounds should be administered first and which should be administered second, and how much time should elapse between administrations of the compounds.
  • factors that effect when the compounds are administered to the patient include, for example, (a) the time(s) that provides the best efficacy for the compound being administered, (b) the time(s) that provides the fewest side effects for the compound being administered, (c) the dosage of the compound, (d) the route of administration of the compound, (e) the disease or disorder being treated, (f) the patient being treated, (g) the in vivo relationship of the compounds being administered, and other such factors known in the art.
  • the time intervals for sequential administration are chosen so that the effect on the disease or disorder being treated in the combined use of the active ingredients is greater than additive when compared to the effect which would be obtained by use of only one of the active ingredients.
  • Combination refers to the AMPA receptor antagonist and the second active ingredient (e.g., antiparkinsonian agents, antimovement disorder agents) being administered separately as distinct pharmaceutical compositions or formulations.
  • the pharmaceutical compositions or formulations can have the same or different modes of administration.
  • “Monotherapy” is a therapy which uses only one active ingredient (e.g., an AMPA receptor antagonist) for treatment and/or prophylaxis of a disease or disorder.
  • an active ingredient e.g., an AMPA receptor antagonist
  • Combination therapy is a therapy where two or more active ingredients are administered separately or are administered in the form of a pharmaceutical composition for the treatment and/or prophylaxis of a disease.
  • “Therapeutically effective amount” refers to the amount of the active ingredient that is necessary for the treatment and/or prophylaxis of a disease.
  • the term “therapeutically effective amount” refers to the amount of active ingredients that are necessary for treatment and/or prophylaxis of a disease and includes, for example: (a) a therapeutically effective amount of a first active ingredient and a therapeutically effective amount of a second active ingredient (i.e., the amount of each active ingredient that would be used for monotherapy for the treatment and/or prophylaxis of a disease is used for the combination therapy); (b) a therapeutically effective amount of a first active ingredient and a sub-therapeutic amount of a second active ingredient, which in combination effectively provide for treatment and/or prophylaxis of a disease (e.g., the sub-therapeutic amount of the second active ingredient can be used in combination therapy to achieve a result that would be equal to or greater than the result that the second active ingredient would achieve if it was used
  • the same therapeutic/sub-therapeutic amounts can be used when there are three or more active ingredients used in combination therapy.
  • active ingredients used in combination therapy.
  • Kits also known as Commercial packages, can include a combination of (i) a first pharmaceutical composition or formulation comprising the AMPA receptor antagonist; (ii) an optional second pharmaceutical composition or formulation comprising the second active ingredient; (iii) instructions for using the pharmaceutical compositions or formulations for treating or preventing or delay the onset of the disease; and (iv) optionally other materials to administer the pharmaceutical compositions or formulations (e.g., syringes, diluents, medical gloves, hand sanitizers, and the like); to monitor drug levels in the body; to support patient compliance with medication dosing; or to monitor the status of the disease.
  • the kit can supply enough medication and materials for days, weeks or months.
  • kits can include (i) pharmaceutical composition or formulation comprising an AMPA receptor antagonist and optionally a second active ingredient; (ii) instructions for using the pharmaceutical composition or formulation for treating or preventing or delay the onset of the disease; and (iii) optionally other materials to administer the pharmaceutical compositions or formulations (e.g., syringes, diluents, medical gloves, hand sanitizers, and the like); to monitor drug levels in the body; to support patient compliance with medication dosing; or to monitor the status of the disease.
  • the kit can supply enough medication and materials for days, weeks or months.
  • the solvate is well known in the art.
  • the solvate is preferably a pharmaceutically acceptable solvate.
  • the pharmaceutically acceptable solvate may be either a hydrate or a nonhydrate, but preferably a hydrate.
  • the solvent such as water, alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide, dimethyl sulfoxide (DMSO) or the like may be used.
  • “Hydrate” refers to a compound containing a molecule of water of crystallization.
  • the molecule of water of crystallization can be an integer of 1 or more, such as 1 to 10; or can be any fraction greater than 0 or a fraction of an integer from 1 to 10.
  • the hydrate may be represented as compound » %H 2 O; compound* '/2H 2 O; compound*%H 2 O; compound*2H 2 O; compounds !4H 2 O; compound*6H 2 O; and the like.
  • the "compound” can be any described herein, such as 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one.
  • “Pharmaceutically acceptable salts” are well known in the art and include those of inorganic acids, such as hydrochloride, sulfate, hydrobromide and phosphate; and those of organic acids, such as formate, tartrate, acetate, trifluoroacetate, methanesulfonate, benzenesulfonate and toluenesulfonate.
  • the compounds of the invention can form, for example, alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic amine salts, such as a salt with trimethyl-amine, triethylamine, pyridine, picoline, dicyclohexylamine or N 5 N'- dibenzylethylenediamine.
  • alkali metal salts such as sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • organic amine salts such as a salt with trimethyl-amine, triethylamine, pyridine, picoline, dicyclohexylamine or N 5 N'- dibenzylethylenediamine.
  • the invention provides methods for the treatment and/or prophylaxis of Parkinson's disease and movement disorders using at least one AMPA receptor antagonist and, optionally, a second active ingredient useful for treating these diseases and disorders.
  • Parkinson's disease is a neurological syndrome usually resulting from deficiency of the neurotransmitter dopamine as the consequence of degenerative, vascular, or inflammatory changes in the basal ganglia, and is characterized by motor dysfunctions, cognitive dysfunctions, and/or dementia.
  • Motor dysfunctions associated with Parkinson's disease may include, for example, one or more of resting tremor, rigidty, bradykinesia, postural instability, parkinsonism, and dyskinesia.
  • Methods for the treatment and/or prophylaxis of Parkinson's disease include the treatment and/or prophylaxis of one or more symptoms of Parkinson's disease.
  • Parkinsonian syndrome also called secondary parkinsonism, refers to any condition that causes any combination of the types of movement abnormalities seen in Parkinson's disease. Parkinsonian syndrome may be caused by a stroke, encephalitis, meningitis, progressive supranuclear palsy, corticobasal degeneration, multiple systems atrophy, medications (e.g., antipsychotics such as haloperidol, metoclopramide, and phenothiazine medications; narcotics; anesthesia agents; toxins, such as carbon monoxide; MPTP). Symptoms of parkinsonian syndrome may include stiffness of the trunk, arms, or legs, a decrease in facial expression, soft voice, tremor, some forms of paralysis, and problems with movement control.
  • medications e.g., antipsychotics such as haloperidol, metoclopramide, and phenothiazine medications; narcotics; anesthesia agents; toxins, such as carbon monoxide; MPTP.
  • Movement disorders refer to any movement disorder known in the art.
  • exemplary movement disorders and symptoms of movements disorders include hypokinetic movement disorders, hyperkinetic movement disorders. These disorders are further divided into Parkinson's disease, spinocerebellar degeneration, multiple system atrophy, progressive supranuclear palsy, Parkinsonian syndrome, Huntington's disease, Lewy body disease, Tourette syndrome, and restless leg syndrome. Symptoms of these disorders are tardive dyskinesia, tics, dystonia, myoclonus, spasticity, chorea, ballism, ataxia, akathisia, athetosis, rigidity, and tremors.
  • Methods for treatment and/or prophylaxis of a movement disorder include the treatment or prophylaxis of one or more symptoms of the movement disorder.
  • Hypokinetic movement disorders are those in which there is a reduced amount of intentional motor activity, generally it is an abnormally reduced amount of activity.
  • the symptoms of hypokinetic movement disorders include a rigid, stone-like face; decreased limb motion during walking; and stiff turning movements. These features are classified as “bradykinesia,” while “akinesia” is the absence of purposeful movement.
  • Hyperkinetic movement disorders are characterized by an increased amount of motor activity, generally the increased motor activity is significant and/or excessive. Hyperkinetic movements disorders include involuntary movement disorders. “Hyperkinetic movement disorders” are generally characterized by two types of behavior: rhythmical and irregular.
  • “Tremor” is a rhythmic movement that is further divided into three forms: rest, postural, and intention. Rest tremor is most prominent when an individual is at rest and decreases with voluntary activity. Postural tremor occurs when an individual attempts to support a position against gravity (such as holding an arm outstretched). Intention tremor occurs during voluntary movement toward a specific target. Involuntary movements are classified by their speed and site of occurrence. "Tics” are rapid irregular movements that are controlled with voluntary effort. The types of rapid irregular movements that cannot be controlled voluntarily are called chorea, ballism, and myoclonus. "Chorea” is a rapid, jerking movement that most often affects the face or limbs.
  • “Ballism” is the sudden and extreme swinging of a limb.
  • “Myoclonus” is a rapid, irregular movement that usually occurs for a short period of time. It usually occurs when the person is at rest, and it often affects more than one area of the body at a time.
  • Huntington's disease characterized by chorea-type movements. Huntington's disease results from genetically programmed degeneration of neurons in certain areas of the brain. This degeneration causes uncontrolled movements (e.g., chorea), loss of intellectual faculties, and emotional disturbance. Huntington's disease is a familial disease, passed from parent to child through a mutation in the normal gene.
  • “Akathisia” is a hyperkinetic movement disorder characterized by restlessness and a desire to move in order to relieve uncomfortable sensations.
  • the uncomfortable sensations may include a feeling of crawling, itching, stretching, or creeping, usually in the legs.
  • RLS Painless leg syndrome
  • a desire to move the limbs often associated with paresthesia or dysesthesia, (2) symptoms exacerbated by rest and relieved by activity, (3) motor restlessness, and (4) nocturnal worsening of symptoms.
  • “Athetosis” is a hyperkinetic movement disorder characterized by slow, writhing, continuous, uncontrollable movement of the arms and legs.
  • Tardive dyskinesia is a neurological syndrome caused by the long-term use of neuroleptic drugs. Neuroleptic drugs are generally prescribed for psychiatric disorders, as well as for some gastrointestinal and neurological disorders. Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements. Features of the disorder may include grimacing, tongue protrusion, lip smacking, puckering and pursing, and rapid eye blinking. Rapid movements of the fingers, arms, legs, and trunk may also occur. "Dystonia” is a movement disorder that causes the muscles to contract and spasm involuntarily because the neurological mechanism that makes muscles relax when they are not in use does not function properly. Opposing muscles often contract simultaneously as if they are "competing" for control of a body part. The involuntary muscle contractions force the body into repetitive and often twisting movements as well as awkward, irregular postures.
  • Ataxia is marked by problems with coordination because parts of the nervous system that control movement and balance are affected. Ataxia may affect the fingers, hands, arms, legs, body, speech, and eye movements. "Ataxia” is often used to describe a symptom of incoordination which can be associated with infections, injuries, other diseases, or degenerative changes in the central nervous system. Most disorders that result in ataxia cause cells in the part of the brain called the cerebellum to degenerate or atrophy. Sometimes the spine is also affected. The terms “cerebellar degeneration” and “spinocerebellar degeneration” are used to describe changes that have taken place in a person's nervous system. Cerebellar and spinocerebellar degeneration have many different causes.
  • Tourette Syndrome is a neurological disorder defined by multiple motor and/or vocal tics lasting for more than one year.
  • the first symptoms usually are involuntary movements (i.e., tics) of the face, arms, limbs or trunk. These tics are frequent, repetitive and rapid. These involuntary tics may also be complicated, involving the entire body, such as kicking and stamping. Many persons report what are described as premonitory urges, e.g., the urge to perform a motor activity. Other symptoms such as touching, repetitive thoughts and movements and compulsions can occur. Tourette syndrome may also be characterized by verbal tics. These verbal tics (vocalizations) usually occur with the movements; later they may replace one or more motor tics.
  • vocalizations include grunting, throat clearing, shouting and barking.
  • the verbal tics may also be expressed as coprolalia (the involuntary use of obscene words or socially inappropriate words and phrases) or copropraxia (obscene gestures).
  • MSA Multiple system atrophy
  • striatonigral degeneration sporadic olivopontocerebellar atrophy
  • Shy-Drager syndrome a progressive neurodegenerative disorder characterized by symptoms of autonomic nervous system failure (such as lightheadedness or fainting spells, constipation, erectile failure in men, and urinary retention) combined with tremor and rigidity, slurred speech, and/or loss of muscle coordination.
  • Spasticity is a condition in which certain muscles are continuously contracted. This contraction causes stiffness or tightness of the muscles and may interfere with movement, speech, and manner of walking. Spasticity is usually caused by damage to the portion of the brain or spinal cord that controls voluntary movement.
  • Spasticity may occur in association with spinal cord injury, multiple sclerosis, cerebral palsy, damage to the brain because of lack of oxygen, brain trauma, severe head injury, and metabolic diseases such as adrenoleukodystrophy, amyotrophic lateral sclerosis, and phenylketonuria.
  • Symptoms of spasticity may include hypertonicity (increased muscle tone), clonus (a series of rapid muscle contractions), exaggerated deep tendon reflexes, muscle spasms, scissoring (involuntary crossing of the legs), and fixed joints. The degree of spasticity varies from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms.
  • Lewy body disease is also known as diffuse Lewy body disease, Lewy body dementia, or dementia with Lewy bodies.
  • Lewy body disease is characterized by one or more of (i) parkinsonian syndrome; (ii) mental decline: reduced alertness and lowered attention span; (iii) recurrent visual hallucinations, usually related to people or animals; (iv) poor response to antipsychotic medications known as neuroleptics, (v) increasing problems handling the tasks of daily living; (vi) repeated falls; (vii) sleep disturbances, including insomnia and acting out dreams; (viii) delusions or depression; and (ix) fluctuations in autonomic processes, including blood pressure, body temperature, urinary difficulties, constipation, and difficulty swallowing.
  • the AMPA receptor antagonist used in the methods and compositions described herein may be any known in the art.
  • Exemplary AMPA receptor antagonists, all of which are active ingredients, include 1,2-dihydropyridine compounds, quinoxalinedione aminoalkylphosphonates, and the like.
  • the AMPA receptor antagonist may be becampanel, EGIS 8332 (7- acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-l,3-dioxolo[4,5-h][2,3]benzodiazepine-8- carbonitrile); GYKI 47261 (4-(7-chloro-2-methyl-4H-3,10,10a-triaza-benzo[f]azulen-9- yl)phenylamine)); irampanel (N,N-dimethyl-2-[2-(3-phenyl-l ,2,4-oxadiazol-5- yl)phenoxy]ethanamine); KRP 199 ((7-[4-[[[[4-carboxyphenyl)-amino]carbonyl]oxy]methyl]- lH-imidazol-l-yl]-3,4-dihydro-3-oxo-6-(trifluoromethyl)
  • the AMPA receptor antagonist is a 1,2-dihydropyridine compound.
  • the 1 ,2-dihydropyridine compound used in the methods and compositions described herein may be any known in the art.
  • the term "1,2-dihydropyridine compound” includes 1,2- dihydropyridine compounds, pharmaceutically acceptable salts of 1 ,2-dihydropyridine compounds, stereoisomers of 1 ,2-dihydropyridine compounds, pharmaceutically acceptable salts of stereoisomers of 1 ,2-dihydropyridine compounds, hydrates of 1 ,2-dihydropyridine compounds, hydrates of pharmaceutically acceptable salts of 1 ,2-dihydropyridine compounds, stereoisomers of hydrates of 1 ,2-dihydropyridine compounds, and stereoisomer of hydrates of pharmaceutically acceptable salts of 1 ,2-dihydropyridine compounds.
  • the 1 ,2-dihydropyridine compound used in the methods and compositions described herein may be a compound of Formula (I)
  • Q is NH, O or S
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, C ]-6 alkyl, or -X-A;
  • X is a single bond, an optionally substituted Ci -6 alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-CO-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(0) m -, -S(O) n -N(R 12 )-, -CH 2 -S(OV, -S(O) C -CH 2 -, -CH 2 -O-, -0-CH 2 -, -N(R 13 )-CO-N(R 14 )- or -N(R
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen, Ci -6 alkyl, or Ci -6 alkoxy; m, n, p and q are each independently an integer of O, 1 or 2;
  • A is an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 3-8 cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted C 6-I4 aromatic hydrocarbocyclic ring, or an optionally substituted 5- to 14-membered aromatic heterocyclic ring; provided that 3 groups among R 1 , R 2 , R 3 , R 4 and R 5 are -X-A; and that the residual 2 groups among R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen, halogen, or C 1-6 alkyl.
  • the following compounds are excluded from the scope of the compound of Formula (I): (1) when Q is O; R 1 and R 5 are hydrogen; and R 2 , R 3 and R 4 are phenyl; (2) when Q is O; R 1 and R 4 are hydrogen; and R 2 , R 3 and R 5 are phenyl; and (3) when Q is O; R 1 and R 2 are hydrogen; and R 3 , R 4 and R 5 are phenyl.
  • the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is a compound of Formula (II): wherein
  • Q is NH, O or S
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci -6 alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(0) m -, -S(O) n -N(R 12 )-, -CH 2 -S(OV, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -, -N(R I 3 )-CO
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 1 1 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen, Ci -6 alkyl, or Ci -6 alkoxy; m, n, p and q are each independently an integer of O, 1 or 2;
  • a 1 , A 2 and A 3 are each independently an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 3-8 cycloalkenyl, an optionally substituted 5- to 14-membered non- aromatic heterocyclic ring, an optionally substituted C 6-I4 aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and
  • R 17 and R 18 are each independently hydrogen, halogen, or Ci -6 alkyl.
  • the invention provides the compound of Formula (II) wherein X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci -6 alkylene, an optionally substituted C 2-6 alkenylene, or an optionally substituted C 2-6 alkynylene.
  • the substituents may be one or more of -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-,
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 1 1 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, or Ci -6 alkoxy; m, n, p and q are each independently an integer of O, 1 or 2;
  • a 1 , A 2 and A 3 are each independently an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 3-8 cycloalkenyl, an optionally substituted 5- to 14-membered non- aromatic heterocyclic ring, an optionally substituted C 6 - I4 aromatic hydrocarbocyclic ring, or an optionally substituted 5- to 14-membered aromatic heterocyclic ring.
  • the substituents for the 1 ,2-dihydropyridine compounds of the invention may be one or more of hydroxy; halogen; nitrile; nitro; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl [wherein the alkyl, alkenyl, and alkynyl can independently and optionally be substituted with one or more groups selected from hydroxy, nitrile, halogen, Ci -6 alkylamino, di(Ci -6 alkyl) amino, C 2-6 alkenylamino, di(C 2-6 alkenyl)amino, C 2-6 alkynylamino, di(C 2-6 alkynyl)amino, N-Ci -6 alkyl-N-C 2-6 alkenylamino, N-Ci -6 alkyl-N-C 2-6 alkynylamino, N-C 2-6 alkenyl-N-C 2-6 alkynylamino, aralkyl
  • the invention provides compounds of Formula (II) wherein A 1 , A 2 and A 3 are each independently an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 3-8 cycloalkenyl or an optionally substituted 5- to 14-membered non-aromatic hetero ring. In another embodiment, the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently an optionally substituted C 6-H aromatic hydrocarbon ring or an optionally substituted 5- to 14-membered aromatic hetero ring.
  • the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, naphthyl, quinolyl, iso-quinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrol idinyl, piperidinyl, piperazinyl or morpholyl; any of which may optionally have substituents.
  • the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently selected from:
  • the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently substituted with hydroxyl, halogen, amino, or nitrile. In another embodiment, the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently hydroxyl, halogen, amino, nitrile, or nitro. In another embodiment, the invention provides the compound of Formula (II) wherein Q is oxygen.
  • the invention provides the compounds of Formula (I) or (II) wherein X 1 , X 2 and X 3 are each a single bond.
  • the invention provides the compounds of Formula (I) or (II) wherein R 17 and R 18 are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or iso- propyl.
  • the invention provides the compounds of Formula (I) or (II) wherein R 17 and R 18 are each hydrogen.
  • the halogen atom indicates fluorine, chlorine, bromine, iodine and the like, and the preferable atoms include fluorine, chlorine and bromine.
  • the Ci -6 alkyl indicates an alkyl having 1 to 6 carbons, and examples include linear chain or branched chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2- ethylpropyl, n-hexyl, l-methyl-2-ethylpropyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1- propylpropyl, 1 -methylbutyl, 2-methylbutyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl, 2,2- dimethyl
  • the C 2-6 alkenyl indicates an alkenyl group having 2 to 6 carbons, and examples include vinyl, allyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl- 1-propenyl, 3-methyl- 1-propenyl, 2-methyl-2-propenyl, 3- methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6- hexadienyl, and the like.
  • the C 2-6 alkynyl indicates an alkynyl group having 2 to 6 carbons, and examples include ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl- 1-propynyl, 1 -ethynyl-2-propynyl, 2- methyl-3-propynyl, 1-pentynyl, 1-hexynyl, 1 ,3-hexadiynyl, 1,6-hexadiynyl, and the like.
  • the Ci -6 alkoxy indicates an alkoxy group having 1 to 6 carbons, and examples include methoxy, ethoxy, n- propoxy, iso-propoxy, sec-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy, sec-pentyloxy, n-hexoxy, iso-hexoxy, 1 , 1 -dimethylpropoxy, 1 ,2-dimethylpropoxy, 2,2-dimethylpropoxy, 2-ethylpropoxy, 1 -methyl-2-ethylpropoxy, 1 -ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1 , 1 ,2-trimethylpropoxy, 1 , 1 -dimethylbutoxy, 1,2-dimethylbutoxy, 2,2- dimethylbutoxy, 2,3-dimethylbutoxy, 1,3-dimethylbutoxy, 1,3-dimethylbutoxy, 1,3-
  • the C 2-6 alkynyloxy indicates an alkynyloxy group having 2 to 6 carbon atoms, and examples include ethynyloxy, 1 - propynyloxy, 2-propynyloxy, 1 -butynyloxy, 2-butynyloxy, 3-butynyloxy, 1 -methyl-2- propynyloxy, l-ethyl-2 -propynyloxy, l-ethynyl-2-propynyloxy, 1 -pentynyloxy, 1 -hexynyloxy, 1,3-hexadiynyloxy, 1,6-hexadiynyloxy, and the like.
  • the C 2-6 alkenyloxy indicates an alkenyloxy group having 2 to 6 carbons, and examples include vinyloxy, 2- propenyloxy, 1-propenyloxy, 2-propenyloxy, iso-propenyloxy, 2-methyl-l-propenyloxy, 3- methyl- 1-propenyloxy, 2 -methyl -2-propenyloxy, 3-methyl-2-propenyloxy, 1 -butenyloxy, 2- butenyloxy, 3-butenyloxy, 1-pentenyloxy, 1 -hexenyloxy, 1 ,3-hexadienyloxy, 1 ,6-hexadienyloxy, and the like.
  • the C 3-8 cycloalkyl indicates a cycloalkyl group composed of 3 to 8 carbon atoms, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • the C 3-8 cycloalkenyl indicates a cycloalkenyl group composed of 3 to 8 carbon atoms, and examples include cyclopropen-1-yl, cyclopropen-3-yl, cyclobuten-1-yl, cyclobuten-3-yl, 1 ,3- cyclobutadien-1-yl, cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadien-l- yl, l,3-cyclopentadien-2-yl, l,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl, cyclohexen-4-yl, 1 ,3-cyclohexadien-l-yl, l,3-cyclohexadien-2-yl, l,
  • the 5- to 14- membered non-aromatic heterocyclic ring means a mono-cyclic, di-cyclic, or tri-cyclic 5- to 14- membered non-aromatic heterocyclic ring which contains one or more hetero atoms selected from nitrogen, sulfur, and oxygen.
  • Specific examples include pyrrolidinyl, pyrrolyl, piperidinyl, piperazinyl, imidazolyl, pyrazolidyl, imidazolidyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolinyl, dihydrofuryl, dihydropyranyl, imidazolinyl, oxazolinyl, and the like.
  • a group derived from a pyridone ring and a non-aromatic condensed ring are also included in the non-aromatic heterocyclic ring.
  • the C 6-I4 aromatic hydrocarbocyclic ring and the aryl mean an aromatic hydrocarbocyclic ring which is composed of 6 to 14 carbon atoms, a mono-cyclic ring, and a condensed di-cyclic, tri-cyclic and the like.
  • phenyl indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl, indathenyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, cyclopentacyclooctenyl, benzocyclooctenyl and the like.
  • the 5- to 14- membered aromatic heterocyclic ring and the heteroaryl ring mean mono-cyclic, di-cyclic, or tricyclic 5- to 14-membered aromatic heterocyclic ring which contain one or more hetero atoms selected from nitrogen, sulfur, and oxygen.
  • aromatic heterocyclic rings containing nitrogen such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl, benzimidazolyl, indolyl, iso-indolyl, indolizinyl, prenyl, indazolyl, quinolyl, iso-quinolyl, quinoliziyl, phthalazyl, naphthylidinyl, quinoxalyl, quinazolinyl, cynnolinyl, pteridinyl, imidazotriazinyl, pyrazinopyridazinyl, acridinyl, phenanthridinyl, carbazolyl, carbazolinyl, perimidinyl, phenanthrolinyl, phen
  • the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is a compound of Formula (III):
  • the invention provides the compounds of Formula (III) wherein A 1 , A 2 and A 3 are each independently an optionally substituted C 6-I4 aromatic hydrocarbon ring or 5- to 14-membered aromatic hetero ring.
  • the invention provides the compounds of Formula (III) wherein A 1 , A 2 and A 3 are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, naphthyl, quinolyl, iso- quinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrolidinyl, piperidinyl, piperaziny
  • the invention provides the compounds of Formula (III) wherein A 1 , A 2 and A 3 are each independently selected from: each of which may optionally be substituted.
  • the invention provides the compounds of Formula (III) wherein the bonding site of the substituent at A 1 , A 2 and A 3 are in the ⁇ -position of the carbon atom bonding to the group X 1 , X 2 and X 3 , respectively.
  • the invention provides the compounds of Formula (III) wherein X 1 , X 2 and X 3 are single bonds.
  • the invention provides the compounds of Formula (III) wherein R 7 and R 18 are hydrogen.
  • the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is Compound A:
  • the IUPAC name for Compound A is 2-(2-oxo-l-phenyl-5-pyridin-2-yl-l,2-dihydropyridin-3- yl)benzonitrile.
  • Compound A may also be referred to as 3-(2-cyanophenyl)-5-(2-pyridyl)-l- phenyl-l,2-dihydropyridin-2-one.
  • Compound A is also known as perampanel.
  • the terms "Compound A,” "2-(2-oxo-l-phenyl-5-pyridin-2-yl-l ,2-dihydropyridin- 3-yl)benzonitrile,” "3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2 -one,” and “perampanel” are intended to include pharmaceutically acceptable salts thereof, hydrates thereof, and hydrates of pharmaceutically acceptable salts thereof.
  • the 1 ,2-dihydropyridine compounds that are useful in the methods and compositions of the invention are 3-(2-cyanophenyl)-5-(2-methylsulfonylaminophenyl)-l- phenyl- 1 ,2-dihydropyridin-2-one; 3-(2-chloro-3-pyridyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one; 3- (2-cyanophenyl)-5-(2-pyridyl)-l -(3-nitrophenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)- 5-(2-pyridyl)- 1 -(3-aminophenyl)- 1 ,2-dihydropyridin
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) at least one other active ingredient that can be used to treat Parkinson's disease or movement disorders, and (iii) at least one pharmaceutically acceptable excipient.
  • the invention also provides combinations comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist and (ii) at least one other active ingredient that can be used to treat Parkinson's disease or movement disorders; wherein the compounds may be administered separately (e.g., simultaneously, sequentially) to a patient to treat the diseases or disorders described.
  • kits e.g., commercial packages
  • the AMPA receptor antagonist can be any described herein.
  • the 1 ,2-dihydropyridine compound can be a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or Compound A.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) 3-(2- cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one; (ii) at least one other active ingredient that can be used to treat Parkinson's disease or movement disorders; and (iii) at least one pharmaceutically acceptable excipient.
  • One or more other active ingredients can be used in conjunction with the AMPA receptor antagonists of the invention for the treatment or prophylaxis of Parkinson's disease and movement disorders.
  • active ingredients useful to treat Parkinson's disease or movement disorders include entacapone/levodopa/carbidopa (e.g., STALEVO®; STAVELO®); entacapone/levodopa/benserazide; pramipexole (e.g., BI-SIFROL®; FIROL®; MIRAPEX®;
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) optionally one or more other active ingredients useful to treat Parkinson's disease or movement disorders, and (iii) at least one pharmaceutically acceptable excipient.
  • the invention also provides combinations comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist and (ii) optionally one or more other active ingredients useful to treat Parkinson's disease or movement disorders; wherein the compounds may be administered separately (e.g., simultaneously, sequentially) to a patient to treat the diseases or disorders described.
  • kits comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) optionally one or more other active ingredients useful to treat Parkinson's disease or movement disorders; and (iii) instructions for the simultaneous, separate or sequential use of (i) and (ii) in the treatment of the diseases and disorders described herein.
  • the AMPA receptor antagonist can be any described herein.
  • the 1 ,2-dihydropyridine compound can be a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or Compound A.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) 3-(2- cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2 -one; (ii) optionally one or more other active ingredients useful to treat Parkinson's disease or movement disorders; and (iii) at least one pharmaceutically acceptable excipient.
  • the invention provides methods for the treatment and/or prophylaxis of Parkinson's disease, movement disorders and one or more symptoms of movement disorders in a patient in need thereof by administering a therapeutically effective amount of: (a) at least one AMPA receptor antagonist, and (b) optionally one or more other active ingredients useful to treat Parkinson's disease or movement disorders.
  • the methods for the treatment of Parkinson's disease, movement disorders and one or more symptoms of Parkinson's disease or movement disorders include (i) methods for reducing the frequency of Parkinson's disease, a movement disorder, or one or more symptoms of Parkinson's disease or a movement disorder, (ii) methods for reducing the severity of Parkinson's disease, a movement disorder, or one or more symptoms of Parkinson's disease or a movement disorder, (iii) methods for reducing the duration of Parkinson's disease, a movement disorder, or one or more symptoms of Parkinson's disease or a movement disorder, (iv) methods for reducing the frequency and severity of Parkinson's disease, a movement disorder, or one or more symptoms of Parkinson's disease or a movement disorder, (v) methods for reducing the frequency and duration of Parkinson's disease or a movement disorder, or one or more symptoms of Parkinson's disease or a movement disorder, (vi) methods for reducing the severity and duration of Parkinson's disease, a movement disorder, or one or more symptoms of Parkinson's disease or a movement disorder, and
  • the dosage form of the formulation included in the combination, kit and/or pharmaceutical composition of the invention is not particularly limited.
  • the combination, kit and/or pharmaceutical composition of the invention is useful as a combination, kit and/or a pharmaceutical composition for treating neuropathic pain; for the prophylaxis of neuropathic pain; and for delaying the onset of neuropathic pain.
  • the combination, kit and/or pharmaceutical composition of the invention may be used as a drug for treating neuropathic pain; for the prophylaxis of neuropathic pain; and for delaying the onset of neuropathic pain.
  • the combination, kit and/or pharmaceutical composition of the invention may be administered to a patient.
  • the combination, kit and/or pharmaceutical composition of the invention may be used through oral or parenteral administration.
  • the given dose of the compound of the invention differs depending on the degree of the symptom, age, sex, weight and sensitivity difference of the patient, administration mode, administration period, administration interval, nature, prescription and the type of the pharmaceutical formulation, and the type of the active element.
  • the pharmaceutical composition of the invention may be made into various forms, for example, into solid oral formulations, injectable solution or the like.
  • the AMPA receptor antagonists and one or more other active ingredients of the invention can be administered orally, topically, parenterally, by inhalation (nasal or oral), or rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral includes subcutaneous, intravenous, intramuscular, intrathecal, intrasternal injection, or infusion techniques.
  • the daily dose of the AMPA receptor antagonists of the invention is usually 30 ⁇ g/day to 10 g/day; 100 ⁇ g/day to 5 g/day; or 100 ⁇ g/day to 100 mg/day, in the case of oral administration.
  • the daily dose is usually 30 ⁇ g/day to 1 g/day; 100 ⁇ g/day to 500 mg/day; or 100 ⁇ g/day to 30 mg/day.
  • the compounds are administered once daily or in several portions a day.
  • the numerical weight refers to the weight of the 1 ,2-dihydropyridine, exclusive of any salt, counterion, hydrate, and the like. Therefore to obtain the equivalent of 500 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1,2- dihydropyridin-2-one, it would be necessary to use more than 500 mg of a pharmaceutically acceptable salt and/or hydrate of the compound, due to the additional weight of the pharmaceutically acceptable salt and/or hydrate.
  • the daily dose of the other active ingredients that are useful for treating Parkinson's disease and movement disorder are usually 0.25 mg/day to 4.5 mg/day, 0.5 mg/day to 4.5 mg/day or 1.5 mg/day to 4.5 mg/day for Pramipexole; 0.25 mg/day to 9 mg/day, 1 mg/day to 9 mg/day or 2 mg/day to 9 mg/day for Ropinirole; or 100 mg/day to 1600 mg/day, 100 mg/day to 800 mg/day or 200 mg/day to 800 mg/day for Entacapone.
  • the compounds are administered once daily, in several portions a day or continuously.
  • the numerical weight refers to the weight of the other active ingredients that are useful for treating Parkinson's disease and movement disorder, exclusive of any salt, counterion, and the like. Therefore to obtain the equivalent of the other active ingredients that are useful for treating Parkinson's disease and movement disorder, it would be necessary to use more than above noted amount of drugs, due to the additional weight of the salts.
  • the dose When administered to a child, the dose may possibly be lower than that for an adult.
  • the actual method for administration may fluctuate widely and may depart from the preferred method described herein.
  • any other compounds described herein may be administered in doses well known in the art by reference, for example, to package inserts of commercially available compounds, The Physician's Desk Reference, to patents describing dosing for the compounds, and to journal articles describing dosing for the compounds.
  • the mode of administration is by injection, such as subcutaneous injection, intramuscular injection, intravenous injection, or intra-arterial injection.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the art using suitable dispersing or wetting agents, suspending agents (e.g., methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose, polyoxytehylene sorbitan monolaurate and the like), pH modifiers, buffers, solubilizing agents (e.g., polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, an ethyl ester of castor oil fatty acid, and the like), stabilizers (e.g., sodium sulfite and sodium metasulfite; examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, chlorocresol, and the like), tonic
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally used as a solvent or suspending medium.
  • any bland fixed oil can be used including synthetic mono- or diglycerides, in addition, fatty acids, such as oleic acid, can be used in the preparation of injectables.
  • the preparations can be lyophilized by methods known in the art.
  • an excipient In order to prepare a solid oral formulation, an excipient, and if necessary, a binder, disintegrant, lubricant, colorant, a flavoring agent and the like are added to the principal agent, and then made into a tablet, a coated tablet, granule, fine granule, dispersant, a capsule or the like according to a conventional method.
  • lactose, cornstarch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide or the like may be used as the excipient; for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl cellulose or the like may be used as the binder; for example, magnesium stearate, talc, silica or the like may be used as the lubricant; those that are allowed to be added to drugs may be used as the colorant; and for example, cocoa powder, menthol, aromatic acid, peppermint oil, camphor, cinnamon powder or the like may be used as the flavoring agent.
  • these tablets and granule may be coated appropriately with sugar coating, gelatin coating or else.
  • Solid dosage forms for oral administration can include chewing gum, capsules, tablets, sublingual tablets, powders, granules, and gels.
  • the active compound can be admixed with one or more inert diluents such as lactose or starch.
  • inert diluents such as lactose or starch.
  • such dosage forms can also comprise other substances including lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • the tablets can be prepared with enteric or film coatings, preferably film coatings.
  • the compounds can be admixed with pharmaceutically acceptable carriers known in the art such as, for example, vehicles (e.g., lactose, white sugar, mannitol, glucose, starches, calcium carbonate, crystalline cellulose, silicic acid, and the like), binders (e.g., water, ethanol, myranol, glucose solution, starch solution, gelatin solution, polyvinylpyrrolidone, and the like), disintegrators (e.g., dry starch, sodium, alginate, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, and the like), absorption promoters (e.g., quaternary ammonium base, sodium laurylsulfate, and the like), wetting agents (e.g.
  • vehicles e.g., lactose, white sugar, mannitol, glucose, starches, calcium
  • the tablets can be in the form of a conventional tablet, a molded tablet, a wafer and the like.
  • Sublingual administration refers to the administration in the mouth (e.g., under the tongue, between the cheek and gum, between the tongue and roof of the mouth).
  • the highly vascular mucosal lining in the mouth is a convenient location for the compounds to be administered into the body.
  • the solid dosage form can be packaged as granules or a powder in a pharmaceutically acceptable carrier, where the granules or powder are removed from the packaging and sprinkled on food or mixed with a liquid, such as water or juice, or where the granules are inserted into capsules.
  • the compounds described herein can be mixed with flavoring or sweetening agents.
  • the packaging material can be plastic, coated paper, or any material that prevents water or moisture from reaching the granules and/or powder.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, sublingual solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the compounds can be admixed with various carriers, excipients, pH adjusters, and the like (e.g., water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavoring and coloring agents).
  • carriers e.g., water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavoring and coloring agents.
  • carriers e.g., water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin

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  • Animal Behavior & Ethology (AREA)
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  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur des procédés pour traiter la maladie de Parkinson par l'administration à des patients de quantités thérapeutiquement efficaces d'antagonistes des récepteurs AMPA en combinaison avec un ou plusieurs autres ingrédients actifs utiles pour traiter la maladie de Parkinson. L'invention porte sur des procédés pour traiter des troubles du mouvement par l'administration à des patients de quantités thérapeutiquement efficaces d'antagonistes des récepteurs AMPA, éventuellement en combinaison avec un ou plusieurs autres ingrédients actifs qui sont utiles pour traiter les troubles du mouvement. L'invention porte également sur des compositions pharmaceutiques, sur des coffrets et sur des compositions pharmaceutiques renfermant des quantités thérapeutiquement efficaces d'antagonistes des récepteurs AMPA et, éventuellement, un ou plusieurs autres ingrédients actifs qui sont utiles pour traiter la maladie de Parkinson et/ou les troubles du mouvement.
PCT/JP2008/069820 2007-10-26 2008-10-24 Antagonistes des récepteurs ampa pour la maladie de parkinson et les troubles du mouvement WO2009054544A1 (fr)

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US8304413B2 (en) 2008-06-03 2012-11-06 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
WO2013181292A1 (fr) * 2012-05-29 2013-12-05 Biotie Therapies, Inc. Formulations de nitisinone
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
CN104321057A (zh) * 2012-04-20 2015-01-28 Ucb医药有限公司 用于治疗帕金森病的方法
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
GR1010285B (el) * 2021-05-31 2022-08-24 Elpen Αε Φαρμακευτικη Βιομηχανια, Στερεες φαρμακοτεχνικες μορφες περαμπανελης
CN115282156A (zh) * 2022-09-05 2022-11-04 广东海洋大学 知母皂苷元在制备防治帕金森病的药物中的应用
US11878958B2 (en) 2022-05-25 2024-01-23 Ikena Oncology, Inc. MEK inhibitors and uses thereof

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US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US8304413B2 (en) 2008-06-03 2012-11-06 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
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JP2013507352A (ja) * 2009-10-09 2013-03-04 テバ ファーマシューティカル インダストリーズ リミティド 進行性核上性麻痺の治療のためのラサギリンの使用
WO2011042812A1 (fr) * 2009-10-09 2011-04-14 Stefan Lorenzl Utilisation de rasagiline pour le traitement d'une paralysie supranucléaire progressive
CN104321057A (zh) * 2012-04-20 2015-01-28 Ucb医药有限公司 用于治疗帕金森病的方法
CN104321057B (zh) * 2012-04-20 2016-09-14 Ucb医药有限公司 用于治疗帕金森病的方法
WO2013181292A1 (fr) * 2012-05-29 2013-12-05 Biotie Therapies, Inc. Formulations de nitisinone
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US8889190B2 (en) 2013-03-13 2014-11-18 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10363224B2 (en) 2013-03-13 2019-07-30 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9555005B2 (en) 2013-03-15 2017-01-31 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10172878B2 (en) 2013-03-15 2019-01-08 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones
GR1010285B (el) * 2021-05-31 2022-08-24 Elpen Αε Φαρμακευτικη Βιομηχανια, Στερεες φαρμακοτεχνικες μορφες περαμπανελης
US11878958B2 (en) 2022-05-25 2024-01-23 Ikena Oncology, Inc. MEK inhibitors and uses thereof
CN115282156A (zh) * 2022-09-05 2022-11-04 广东海洋大学 知母皂苷元在制备防治帕金森病的药物中的应用

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